2000 Fiscal Year Annual Research Report

サイトカイン受容体gp130を介するシグナル伝達の解析

Research Project

Project/Area Number	11670321
Research Institution	Osaka University
Principal Investigator	日比正彦大阪大学, 医学系研究科, 助教授 (40273627)
Keywords	gp130 / STAT3 / STAT3 / Pim-1 / c-Myc / Gab1 / 細胞増殖 / ノックインマウス
Research Abstract	gp130は、IL-6ファミリーサイトカインの共通の受容体コンポーネントである。gp130を介するシグナルは大きく、gp130のチロシン759のリン酸化依存性に活性化されるシグナル(SHP2が関与)、YXXQモチーフのチロシンリン酸化依存性に活性化されるSTAT3を介するシグナル、gp130のチロシンリン酸化を介しないシグナル、の三つに分けることができる。1.我々は、細胞株を用いた研究から、gp130を介する細胞増殖シグナルに、チロシン759依存性シグナルとSTAT3シグナルの両方が必要であることを示してきた。本研究では、STAT3の標的遺伝子としてPim遺伝子(Pim-1,2)とc-myc遺伝子が存在し、Pim-1とc-Mycが協調的に機能することで、細胞周期G1-S期移行の制御および細胞死を抑制していることを見出した。また、Pim-1の下流でVCP/Cdc48pが細胞死抑制に機能していることを明らかにした。2.我々は、チロシン759依存性シグナルに関与する分子として、Gab1を同定してきた。本研究では、Gab1欠損マウスの作成を行い、Gab1が胎盤・心臓・皮膚の発生に必須であること、Gab1がgp130のシグナルだけでなく増殖因子EGF,PDGF,HGFのERK MAPキナーゼ活性化へのシグナルに関与していることを見出した。3.また、gp130からのシグナルの生体内での役割を解析するため、チロシン759あるいはYXXQモチーフのチロシンをフェニールアラニンに変異させたgp130を、マウス染色体gp130に置換したマウス(ノックインマウス)を作成し、その解析を行った。その結果、STAT3を介するシグナルが、IgG2a,IgG2b抗体産生・Th1型サイトカイン産生に関与しており、チロシン759を介するシグナルがそれを抑制する方向に働いていることを見出した。

Research Products

(17 results)

All Other

All Publications (17 results)

[Publications] Nishida,K., et al.: "Gab family adapter proteins act downstream of cytokine and growth factor receptors and T and B cell antigen receptors."Blood. 93. 1809-1816 (1999)
[Publications] Fekany,K., et al.: "The zebrafish bozozok locus encodes Dharma, a hemoedomain protein essential for induction of gastrula organizer and dorsoanterior embryonic structures."Development. 126. 1427-1438 (1999)
[Publications] Wickrema,A., et al.: "Engagement of gab1 and gab2 in erythropoietin signaling.J.Biol.Chem."J.Biol.Chem.. 274. 24469-24474 (1999)
[Publications] Nakayama,K., et al.: "A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth."J.Biol.Chem.. 274. 24766-24772 (1999)
[Publications] Ito,M., et al.: "JSAP1, a novel JNK-binding protein that functions as a scaffolding factor in the JNK signaling pathway."Mol.Cell.Biol.. 19. 7539-7548 (1999)
[Publications] Shirogane,T., et al.: "Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and anti-apoptosis."Immunity. 11. 709-719 (1999)
[Publications] Hashimoto,H., et al.: "Zebrafish Dkk1 functions in Forebrain Specification and Axial Mesendoderm Formation."Dev.Biol.. 217. 138-152 (2000)
[Publications] Ohtani,T., et al.: "Dissection of signaling cascades through gp130 in vivo : Reciprocal roles for STAT3-and SHP2-mediated signals in immune responses."Immunity. 12. 95-105 (2000)
[Publications] Shimizu,T., et al.: "Cooperative roles of Bozozok/Dharma and Nodal-related proteins in the formation of the dorsal organizer in zebrafish."Mech.Dev.. 91. 293-303 (2000)
[Publications] Daino,H., et al.: "Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells : possible involvement of STAT3 degradation by proteasome pathway in interleuikin 6-dependent hematopoietic cells."Blood. 95. 2577-2585 (2000)
[Publications] Ito,M., et al.: "A role of Gab1 for heart, placenta, and skin development, and growth factors-and cytokines-induced ERK MAP kinase activation."Mol.Cell.Biol.. 20. 3695-3704 (2000)
[Publications] Hirata,T., et al.: "Novel mix-family homeobox genes in zebrafish and their differential regulation."Biochem.Biophys.Res.Comm.. 271. 603-609 (2000)
[Publications] Hashimoto H., et al.: "Expression of the zinc finger gene fez-like in zebrafish forebrain."Mech.Dev.. 97. 191-195 (2000)
[Publications] Fujii,R., et al.: "Asymmetric p38 activation in zebrafish; its possible role in symmetric and synchrnous cleavage."J.Cell.Biol.. 150. 1335-1347 (2000)
[Publications] Park,H-C., et al.: "Analysis of upstream elements in the HuC promoter leads to the establishment of transgenic zebrafish with fluorescent neurons."Dev.Biol.. 227. 279-293 (2000)
[Publications] Muraoka,O., et al.: "Kheper, a novel ZFH/dEF1 family, regulates the development of the neuroectoderm of zebrafish (Danio rerio)."Dev.Biol.. 228. 29-40 (2000)
[Publications] Ryu,S-L., et al.: "Regulation of dharma/bozozok by the Wnt pathway."Dev.Biol.. (in press.).

2000 Fiscal Year Annual Research Report

サイトカイン受容体gp130を介するシグナル伝達の解析

Principal Investigator

日比 正彦 大阪大学, 医学系研究科, 助教授 (40273627)

Research Products

[Publications] Nishida,K., et al.: "Gab family adapter proteins act downstream of cytokine and growth factor receptors and T and B cell antigen receptors."Blood. 93. 1809-1816 (1999)

[Publications] Fekany,K., et al.: "The zebrafish bozozok locus encodes Dharma, a hemoedomain protein essential for induction of gastrula organizer and dorsoanterior embryonic structures."Development. 126. 1427-1438 (1999)

[Publications] Wickrema,A., et al.: "Engagement of gab1 and gab2 in erythropoietin signaling.J.Biol.Chem."J.Biol.Chem.. 274. 24469-24474 (1999)

[Publications] Nakayama,K., et al.: "A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth."J.Biol.Chem.. 274. 24766-24772 (1999)

[Publications] Ito,M., et al.: "JSAP1, a novel JNK-binding protein that functions as a scaffolding factor in the JNK signaling pathway."Mol.Cell.Biol.. 19. 7539-7548 (1999)

[Publications] Shirogane,T., et al.: "Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and anti-apoptosis."Immunity. 11. 709-719 (1999)

[Publications] Hashimoto,H., et al.: "Zebrafish Dkk1 functions in Forebrain Specification and Axial Mesendoderm Formation."Dev.Biol.. 217. 138-152 (2000)

[Publications] Ohtani,T., et al.: "Dissection of signaling cascades through gp130 in vivo : Reciprocal roles for STAT3-and SHP2-mediated signals in immune responses."Immunity. 12. 95-105 (2000)

[Publications] Shimizu,T., et al.: "Cooperative roles of Bozozok/Dharma and Nodal-related proteins in the formation of the dorsal organizer in zebrafish."Mech.Dev.. 91. 293-303 (2000)

[Publications] Daino,H., et al.: "Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells : possible involvement of STAT3 degradation by proteasome pathway in interleuikin 6-dependent hematopoietic cells."Blood. 95. 2577-2585 (2000)

[Publications] Ito,M., et al.: "A role of Gab1 for heart, placenta, and skin development, and growth factors-and cytokines-induced ERK MAP kinase activation."Mol.Cell.Biol.. 20. 3695-3704 (2000)

[Publications] Hirata,T., et al.: "Novel mix-family homeobox genes in zebrafish and their differential regulation."Biochem.Biophys.Res.Comm.. 271. 603-609 (2000)

[Publications] Hashimoto H., et al.: "Expression of the zinc finger gene fez-like in zebrafish forebrain."Mech.Dev.. 97. 191-195 (2000)

[Publications] Fujii,R., et al.: "Asymmetric p38 activation in zebrafish; its possible role in symmetric and synchrnous cleavage."J.Cell.Biol.. 150. 1335-1347 (2000)

[Publications] Park,H-C., et al.: "Analysis of upstream elements in the HuC promoter leads to the establishment of transgenic zebrafish with fluorescent neurons."Dev.Biol.. 227. 279-293 (2000)

[Publications] Muraoka,O., et al.: "Kheper, a novel ZFH/dEF1 family, regulates the development of the neuroectoderm of zebrafish (Danio rerio)."Dev.Biol.. 228. 29-40 (2000)

[Publications] Ryu,S-L., et al.: "Regulation of dharma/bozozok by the Wnt pathway."Dev.Biol.. (in press.).

日比正彦大阪大学, 医学系研究科, 助教授 (40273627)