2000 Fiscal Year Annual Research Report

v-Src癌化細胞の浸潤・転移に決定的なシグナル伝達系の研究

Research Project

Project/Area Number	12215063
Research Institution	Nagoya University
Principal Investigator	浜口道成名古屋大学, 医学部, 教授 (90135351)
Co-Investigator(Kenkyū-buntansha)	岩本隆司名古屋大学, 医学部, 助手 (60223426) 松田覚名古屋大学, 医学部, 助教授 (50242110)
Keywords	v-Src / 浸潤・転移 / MMP・2 / Ras / MEK1 / MAPK / v-Crk
Research Abstract	我々の主な研究対象とする癌遺伝子srcは、元々ラウス肉腫ウイルスの癌遺伝子として同定されたが、最近その癌原遺伝子c-srcの産物c-Srcキナーゼがヒト大腸癌や乳癌で高率に活性化される事、悪性の臨床症状を示す大腸癌症例で、その活性化を生じる欠損変異が高率に見い出され、ヒト癌の浸潤転移に関与するシグナル伝達系を同定する為に、重要なモデル系であると言える。我々はまずv-Srcキナーゼによるマトリックスメタロプロテイナーゼ(MMP)の分泌活性化機構に関して研究を進めた。その結果、v-Src癌化細胞では、MEK1-MAPKシグナル伝達系がMMPの分泌と活性化に決定的なシグナルである事を、ドミナントネガティブMEK1遺伝子を用いて同定した。更に、同様の系が、v-Crk癌化細胞や、ConA刺激細胞においてもMMPの分泌活性化に必須である事を証明した。v-Srcによって転写抑制を受ける遺伝子を調べ、その内のSHPS-1がMAPキナーゼを介して転写抑制され、その強制発現がv-Src癌化細胞の足場非依存増殖を特異的に抑制する事を見い出した。ヒト癌におけるMEK1-MAPKシグナル伝達系と癌化の相関を調べた結果、乳癌細胞、乳癌組織においてMAPキナーゼを活性化させ、細胞の足場非依存増殖を活性化する新規の因子MAWDを同定した。現在その詳細を解析中である。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Takeshi Senga,Michinari H., et al: "Clustered cvsteine residues in the kinase domain of v-Src : critical role for protein stability, cell transformation and sensitivity to horbimycin A."Oncogene. 19. 273-279 (2000)
[Publications] Satoru Matsuda,Michinari H., et al: "Molecular cloning and characterzation of a novel human gene (HERNA) which encodes a putative RNA-helicase."Biochim.B Biochim.Biophys.Acta .. 1490. 163-169 (2000)
[Publications] Tomotaka Kamei,Michinari H., et al: "c-Cb1 protein in human cancer tissues is frequently tyrosine phosphorylated in a tumor-specific manner."Int.J.Oncogene. 17. 335-339 (2000)
[Publications] Yusuke Ohba,Michinari H., et al: "Rap2 as a Slowly Responding Molecular Switch in the Rap1 Signaling Cascade."Mol.Cell.Biol.. 20. 6074-6083 (2000)
[Publications] Chika Nozaki,Michinari H., et al: "Prognostic impact of telomerase activity in patients with neuroblastoma."Int.J.Oncogene. 17. 341-345 (2000)
[Publications] Kazuya Machida,Michinari H., et al: "Invasion activating caveolin-1 mutation in human scirrhous breast cancers."Cancer Res.. (in press).
[Publications] Aye Aye Thant,Michinari H., et al: "Constitutive activation of MAP kinase kinase (MEK1) is critical and sufficient for the activation of MMP-2."Exp.Cell Res. 254. 180-188 (2000)
[Publications] Satoru M.Michinari H., et al: "Molecular cloning and characterization of human MAWD, a novel protein containig WD-40 repeats frequently overexpressed in breast cancer."Cancer Res.. 60. 13-17 (2000)
[Publications] Kazuya M.Michinari H., et al: "v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells."Oncogene. 19. 1710-1718 (2000)
[Publications] Enbo Liu,Michinari H., et al: "The Ras-MEK1 pathway is critical for the activation of MMP secretion and the invasiveness in v-crk-transformed 3Y1."Cancer Res.. 60. 2361-2364 (2000)
[Publications] Thet Thet Sein,Michinari H., et al: "A role for FAK in the concanavalin A-dependent secretion of Matrix metalloproteinase-2 and-9."Oncogene. 19. 5539-5542 (2000)
[Publications] Takashi Iwamoto,Michinari H., et al: "The JAK-inhibitor, JAB/SOCS-1 selectivity inhibits cytokine-induced, but not v-Src induced JAK-ATAT activation."Oncogene. 19. 4795-4801 (2000)

2000 Fiscal Year Annual Research Report

v-Src癌化細胞の浸潤・転移に決定的なシグナル伝達系の研究

Principal Investigator

浜口 道成 名古屋大学, 医学部, 教授 (90135351)

Research Products

[Publications] Takeshi Senga,Michinari H., et al: "Clustered cvsteine residues in the kinase domain of v-Src : critical role for protein stability, cell transformation and sensitivity to horbimycin A."Oncogene. 19. 273-279 (2000)

[Publications] Satoru Matsuda,Michinari H., et al: "Molecular cloning and characterzation of a novel human gene (HERNA) which encodes a putative RNA-helicase."Biochim.B Biochim.Biophys.Acta .. 1490. 163-169 (2000)

[Publications] Tomotaka Kamei,Michinari H., et al: "c-Cb1 protein in human cancer tissues is frequently tyrosine phosphorylated in a tumor-specific manner."Int.J.Oncogene. 17. 335-339 (2000)

[Publications] Yusuke Ohba,Michinari H., et al: "Rap2 as a Slowly Responding Molecular Switch in the Rap1 Signaling Cascade."Mol.Cell.Biol.. 20. 6074-6083 (2000)

[Publications] Chika Nozaki,Michinari H., et al: "Prognostic impact of telomerase activity in patients with neuroblastoma."Int.J.Oncogene. 17. 341-345 (2000)

[Publications] Kazuya Machida,Michinari H., et al: "Invasion activating caveolin-1 mutation in human scirrhous breast cancers."Cancer Res.. (in press).

[Publications] Aye Aye Thant,Michinari H., et al: "Constitutive activation of MAP kinase kinase (MEK1) is critical and sufficient for the activation of MMP-2."Exp.Cell Res. 254. 180-188 (2000)

[Publications] Satoru M.Michinari H., et al: "Molecular cloning and characterization of human MAWD, a novel protein containig WD-40 repeats frequently overexpressed in breast cancer."Cancer Res.. 60. 13-17 (2000)

[Publications] Kazuya M.Michinari H., et al: "v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells."Oncogene. 19. 1710-1718 (2000)

[Publications] Enbo Liu,Michinari H., et al: "The Ras-MEK1 pathway is critical for the activation of MMP secretion and the invasiveness in v-crk-transformed 3Y1."Cancer Res.. 60. 2361-2364 (2000)

[Publications] Thet Thet Sein,Michinari H., et al: "A role for FAK in the concanavalin A-dependent secretion of Matrix metalloproteinase-2 and-9."Oncogene. 19. 5539-5542 (2000)

[Publications] Takashi Iwamoto,Michinari H., et al: "The JAK-inhibitor, JAB/SOCS-1 selectivity inhibits cytokine-induced, but not v-Src induced JAK-ATAT activation."Oncogene. 19. 4795-4801 (2000)

浜口道成名古屋大学, 医学部, 教授 (90135351)