癌遺伝子産物の生理機能に基づく発癌機構の解析

• Project/Area Number: 06283203
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: The University of Tokyo
• Principal Investigator: 山本 雅 東京大学, 医科学研究所, 教授 (40134621)
• Co-Investigator(Kenkyū-buntansha): 藤元 次郎 東京大学, 医科学研究所, 助手 (60282521) ; 梅森 久視 東京大学, 医科学研究所, 助手 (20242117) ; 松田 覚 (松田 覺) 名古屋大学, 医学部, 講師 (50242110) ; 椎尾 譲 東京大学, 医科学研究所, 学振特別研究員
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥150,000,000 (Direct Cost: ¥150,000,000); Fiscal Year 1999: ¥24,000,000 (Direct Cost: ¥24,000,000); Fiscal Year 1998: ¥24,000,000 (Direct Cost: ¥24,000,000); Fiscal Year 1997: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 1996: ¥28,000,000 (Direct Cost: ¥28,000,000); Fiscal Year 1995: ¥22,000,000 (Direct Cost: ¥22,000,000); Fiscal Year 1994: ¥22,000,000 (Direct Cost: ¥22,000,000)
• Keywords: 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 / 三量体G蛋白質 / リンパ球活性化 / リンパ腫 / 細胞癌化 / シグナル伝達 / 免疫反応 / シナプス可塑性 / 染色体転座 / 免疫寛容 / 癌遺伝子 / Tのシンキナーゼ / リンパ球活性反応 / 中枢神経系 / 増殖因子受容体 / 遺伝子欠損マウス

Research Abstract

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。

Research Products

• [Publications] H. Umemori: "Stimulation of Myelin Basic Protein Gene Transcription by Fyn Tyrosine Kinase for Myelination"J. Neuroscience. 19. 1393-1397 (1999)
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• [Publications] 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)
• [Publications] M. Saito: "Growth factor-mediated Fyn signaling regulates AMPA receptor expression in rodent neocortical neurons"Proc. Natil. Acad. Sci. USA. 96. 2461-2466 (1999)
• [Publications] H. Umemori: "Involvement of protein tyrosine phosphatase in activation of the trimeric G protein Gq/11"Oncogene. 18. 7399-7402 (1999)
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• [Publications] 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)
• [Publications] A. Naito: "Severe osteoperarosis, devective interleukin-1 signaling and lymph mode organogenesis in TRAF6-deficient mice"Genes Cells. 4. 353-362 (1999)
• [Publications] K. Horikawa: "Distinctive roles of Fyn and Lyn in IgD- and IgM-magma-Mediated signaling"International Immunology. 11. 1441-1449 (1999)
• [Publications] 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)
• [Publications] M. Kim: "Molecular cloning and characterization of a novel cbl-family gene, cbl-c"Gene. 239. 145-154 (1999)
• [Publications] H. Umemori: "Involvement of protein tyrosine phosphatase in activation of the trimeric G protein Gq/11"Oncogene. 18. 7399 (1999)
• [Publications] 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).
• [Publications] T.Suzuki: "Essential roles of Lyn in fibronectin-meiated filamentous-actin assembly and cell motility in mast cells." J.Immunol.161. 3964-3701 (1998)
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• [Publications] T.Hayashi: "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn" Nature. 397. 72-76 (1999)
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• [Publications] Hisashi Umemori: "Activation of the G protein Gq/11 through tyrosine phosphorylation of the α subunit." Science. 276. 1878-1881 (1997)
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• [Publications] Dusko Ilic: "Impairment of mobility in endodermal cells by FAK deficiency." Exp.Cell Res.222. 298-303 (1996)
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• [Publications] Onoda,M.: "ErB-2 Expression is Correlated with Poor Prognosis in Osteosarcomas." Cancer. 77. 71-78 (1996)
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• [Publications] Nishizumi,H.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient Mice." Immunity. 3. 549-560 (1995)
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• [Publications] Fujimoto,J.: "brt,a mouse gene encoding a novel receptor-type protein-tyrosine kinase,is preferentially expressed in the brain." Oncogene. 9. 693-698 (1994)
• [Publications] Umemori,H.,: "Initial events of myelination involve Fyn tyrosine kinase signaling." Nature. 367. 572-576 (1994)
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• [Publications] Mizuguchi,G.,: "Independent control of transcription initations from two sites by an initiator-like element and TATA box in the human c-erbB-2 promoter." FEBS Letters. 348. 80-88 (1994)
• [Publications] Fusaki,N.,: "Characterization of p59^<fyn>-mediatedd signal transduction on T cell activation." Int'l Immunol. 6. 1245-1255 (1994)
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• [Publications] Otsuka,M.: "Novel zinc chelators which inhibit the binding of HIV-EPI (HIV enhancer binding protein) to NF-κB recognition sequence." J.Med.Chem.37. 4267-4269 (1994)
• [Publications] Takahashi,T.: "Human A-myb gene encodes a transcriptional activator containing the negative regulatory domains." FEBS Letters. 358. 89-96 (1995)
• [Publications] Kadowaki,Y.: "Dual transcriptional control by Ear3/COUP:Negative regulation through DR1 and positive regulation through a sequence downstream of the transcriptional start site of the mouse mammary tumor virus promoter." Proc.Natl.Acad.Sci.USA.(in press).
• [Publications] Shiota,M.: "Introduction of antibody to p80' a new chimeric protein tyrosine kinase,for the diagnosis of Ki-1 lymphomas with t(2;5) (p23;q35)." Blood.(in press).
• [Publications] Ilic,D.: "Inhibition of fibroblast-like cell differentiation by FAK-deficiency." Biochem.Biophys.Commun.(in press).
• [Publications] Watanabe,N.: "Protein-tyrosine kinase activities of c-Src and c-Yes.and expression of CSK in human benign prostatic hyperplasia and prostate cancer." Jpn.J.Clin.Oncol.(in press).
• [Publications] Yamamoto,T.: "Molecular Biology in Clinical Oncology and Hematology" Martin Dunitz Ltd.(in press),
• [Publications] Yamamoto,T.: "Methods in Enzymology" Academic Press.(in press),