1999 年度実績報告書

癌遺伝子産物の生理機能に基づく発癌機構の解析

研究課題

研究課題/領域番号	06283203
研究機関	東京大学
研究代表者	山本雅東京大学, 医科学研究所, 教授 (40134621)
研究分担者	藤元次郎東京大学, 医科学研究所, 助手 (60282521)
キーワード	チロシンキナーゼ / チロシンフォスファターゼ / Srcファミリー / Cblファミリー / 細胞周期 / Tobファミリー / BMPシグナル / LATS癌抑制遺伝子
研究概要	チロシンりん酸化をはじめとする蛋白質りん酸化反応に着目して、細胞の増殖制御に関する解析を進め、以下の知見を得た。 1.ショウジョウバエがん抑制遺伝子のヒトホモローグLATS2の産物が、細胞周期のG2/M期でキナーゼ活性が高いことを示し、細胞周期制御に関わっている可能性を示唆した。 2.細胞増殖抑制性蛋白質TobはPDGF刺激により、Ras,MAPK経路を介してりん酸化され、そのことで増殖抑制活性が調節される。従ってTobは細胞周期のG0あるいはearly G1で機能していると考えられた。 3.TobはBMP2シグナル伝達に関わり、Tob欠損骨芽細胞ではBMP2反応性が亢進している。その結果、Tob欠損マウスは骨の過形成を示す。 4.Tob2をβ-galに置換したTob2欠損マウスを作成した。Tob2は種々の組織で普遍的に発現するものの、特に小腸細胞、生殖組織で顕著に発現している。 5.B細胞で抗原刺激依存的にLynでりん酸化されるCblは、BLNKとPLCγの会合を阻害し、結果としてPLCγの活性を負に制御している。一方Cbl類似Cbl-b蛋白質はPLCγの活性を正に制御している。 6.Cblに類似するCbl-cを新規にクローニングした。Cbl-cは他のCblファミリーメンバー同様受容体型チロシンキナーゼやSrcファミリーチロシンキナーゼと会合する。 7.ショウジョウバエFakの発現様式の解析から、Fakがインテグリンシグナル伝達系に関わる事を示唆した。

研究成果

(19件)

すべてその他

すべて文献書誌 (19件)

[文献書誌] H. Umemori: "Stimulation of Myelin Basic Protein Gene Transcription by Fyn Tyrosine Kinase for Myelination"J. Neuroscience. 19. 1393-1397 (1999)
[文献書誌] T. Hayashi: "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn"Nature. 397. 72-76 (1999)
[文献書誌] T. Tezuka: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the M-methyl-D-aspartate receptor subunit NR2A"Proc. Natil. Acad. Sci. USA. 96. 435-440 (1999)
[文献書誌] M. Saito: "Growth factor-mediated Fyn signaling regulates AMPA receptor expression in rodent neocortical neurons"Proc. Natil. Acad. Sci. USA. 96. 2461-2466 (1999)
[文献書誌] H. Umemori: "Involvement of protein tyrosine phosphatase in activation of the trimeric G protein Gq/11"Oncogene. 18. 7399-7402 (1999)
[文献書誌] Y. Muto: "Age-related decrease in brain-derived neurotrophic factor gene expression in the brain of the zitter rat with genetic spongiform encephalopathy"Neuroscience Letters. 271. 69-72 (1999)
[文献書誌] C. Hisatsune: "Phosphorylation-dependent interaction of the N-methyl I-D-aspartate receptor e2 subunit with phosphatidylinositol 3-kinase"Genes to Cells. 4. 657-666 (1999)
[文献書誌] D.J. Caughey: "Fractionation of polyclonal antibodies to fragments of a neuroeceptor using three increasingly chaotropic solvents"J. Chromatogr. B. Biomed. Sci. Appl.. 728. 48-57 (1999)
[文献書誌] J. Fujimoto: "Cloning and characterization of dfak56, a homolog of focal adhesion kinase, in drosophila melanogaster"J. Biol. Chem.. 274. 29196-29201 (1999)
[文献書誌] M. Martins-Green: "Tissue specific expression of Yrk kinase: implications for differentiation and inflammation"Int'l. J. Biolchem. and Cell Biol.. (in press).
[文献書誌] Y. Yamaniash: "Role of the ras GAP-associated docking protein p62 dok in negative regulation of B cell receptor-mediated signaling"Genes & Dev.. 14. 11-16 (2000)
[文献書誌] T. Yasuda: "Cbl suppresses B cell receptor-mediated phospholipase c-γ2 activation by regulating BLKN-PLC-γ2 binding"J. Exp. Med.,. (in press).
[文献書誌] N. Tsukamoto: "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40"Proc. Natil. Acad. Sci. USA. 96. 1234-1239 (1999)
[文献書誌] A. Naito: "Severe osteoperarosis, devective interleukin-1 signaling and lymph mode organogenesis in TRAF6-deficient mice"Genes Cells. 4. 353-362 (1999)
[文献書誌] K. Horikawa: "Distinctive roles of Fyn and Lyn in IgD- and IgM-magma-Mediated signaling"International Immunology. 11. 1441-1449 (1999)
[文献書誌] N. Ikematsu: "Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinase"Oncogene. 18. 7432-7441 (1999)
[文献書誌] M. Kim: "Molecular cloning and characterization of a novel cbl-family gene, cbl-c"Gene. 239. 145-154 (1999)
[文献書誌] H. Umemori: "Involvement of protein tyrosine phosphatase in activation of the trimeric G protein Gq/11"Oncogene. 18. 7399 (1999)
[文献書誌] Z. Honda: "Sequential requirements of N-terminal palmitoylation site and SH2 domain of Src family kinases in the initiation and progression of FcεRI signaling"Mol. Cell. Biol.. (in press).

1999 年度 実績報告書

癌遺伝子産物の生理機能に基づく発癌機構の解析

研究代表者

山本 雅 東京大学, 医科学研究所, 教授 (40134621)

研究成果

[文献書誌] H. Umemori: "Stimulation of Myelin Basic Protein Gene Transcription by Fyn Tyrosine Kinase for Myelination"J. Neuroscience. 19. 1393-1397 (1999)

[文献書誌] T. Hayashi: "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn"Nature. 397. 72-76 (1999)

[文献書誌] T. Tezuka: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the M-methyl-D-aspartate receptor subunit NR2A"Proc. Natil. Acad. Sci. USA. 96. 435-440 (1999)

[文献書誌] M. Saito: "Growth factor-mediated Fyn signaling regulates AMPA receptor expression in rodent neocortical neurons"Proc. Natil. Acad. Sci. USA. 96. 2461-2466 (1999)

[文献書誌] H. Umemori: "Involvement of protein tyrosine phosphatase in activation of the trimeric G protein Gq/11"Oncogene. 18. 7399-7402 (1999)

[文献書誌] Y. Muto: "Age-related decrease in brain-derived neurotrophic factor gene expression in the brain of the zitter rat with genetic spongiform encephalopathy"Neuroscience Letters. 271. 69-72 (1999)

[文献書誌] C. Hisatsune: "Phosphorylation-dependent interaction of the N-methyl I-D-aspartate receptor e2 subunit with phosphatidylinositol 3-kinase"Genes to Cells. 4. 657-666 (1999)

[文献書誌] D.J. Caughey: "Fractionation of polyclonal antibodies to fragments of a neuroeceptor using three increasingly chaotropic solvents"J. Chromatogr. B. Biomed. Sci. Appl.. 728. 48-57 (1999)

[文献書誌] J. Fujimoto: "Cloning and characterization of dfak56, a homolog of focal adhesion kinase, in drosophila melanogaster"J. Biol. Chem.. 274. 29196-29201 (1999)

[文献書誌] M. Martins-Green: "Tissue specific expression of Yrk kinase: implications for differentiation and inflammation"Int'l. J. Biolchem. and Cell Biol.. (in press).

[文献書誌] Y. Yamaniash: "Role of the ras GAP-associated docking protein p62 dok in negative regulation of B cell receptor-mediated signaling"Genes & Dev.. 14. 11-16 (2000)

[文献書誌] T. Yasuda: "Cbl suppresses B cell receptor-mediated phospholipase c-γ2 activation by regulating BLKN-PLC-γ2 binding"J. Exp. Med.,. (in press).

[文献書誌] N. Tsukamoto: "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40"Proc. Natil. Acad. Sci. USA. 96. 1234-1239 (1999)

[文献書誌] A. Naito: "Severe osteoperarosis, devective interleukin-1 signaling and lymph mode organogenesis in TRAF6-deficient mice"Genes Cells. 4. 353-362 (1999)

[文献書誌] K. Horikawa: "Distinctive roles of Fyn and Lyn in IgD- and IgM-magma-Mediated signaling"International Immunology. 11. 1441-1449 (1999)

[文献書誌] N. Ikematsu: "Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinase"Oncogene. 18. 7432-7441 (1999)

[文献書誌] M. Kim: "Molecular cloning and characterization of a novel cbl-family gene, cbl-c"Gene. 239. 145-154 (1999)

[文献書誌] H. Umemori: "Involvement of protein tyrosine phosphatase in activation of the trimeric G protein Gq/11"Oncogene. 18. 7399 (1999)

[文献書誌] Z. Honda: "Sequential requirements of N-terminal palmitoylation site and SH2 domain of Src family kinases in the initiation and progression of FcεRI signaling"Mol. Cell. Biol.. (in press).

1999 年度実績報告書

山本雅東京大学, 医科学研究所, 教授 (40134621)