1995 年度実績報告書

がん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	梅森久視東京大学, 医科学研究所, 助手 (20242117) 松田覺東京大学, 医科学研究所, 助手 (50242110)
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 / 細胞癌化 / 染色体転座 / シグナル伝達 / 細胞周期 / シナプス可塑性 / 免疫寛容
研究概要	チロシンキナーゼが関与する細胞がん化機構ならびに細胞増殖調節機構に関する研究とSrc型チロシンキナーゼが神経系免疫系で果たす役割について研究を進め以下の成果を得た。 1.Ki-1リンパ腫で染色体転座によって活性化されているp80alk(ヌクレオフォスミンのアミノ末端側の配列と受容体型チロシンキナーゼAlkの細胞内ドメインの融合蛋白質)が、NIH3T3細胞をトランスフォームすることを示した。またp80alkがIRS1とShcをチロシンりん酸化し、かつそれらと会合することを示した。さらに、p80alkのトランスフォーミング活性にはGrb2との会合が必要であることを示した。 2.我々がErbB-2と相互作用するとして同定したTob蛋白質の抗細胞増殖能を明かにし、その活性がTobとCDK蛋白質の相互作用による細胞周期の抑制によることを示唆した。また、Tob類似蛋白質Tob4とTob5を見い出し、既知のPC3、BTG1を含めこれらが大きなファミリーを形成していることを示した。 3.脳で高い発現を示すfak欠損マウスの解析を相沢らと共同で進め、Fakチロシンキナーゼが細胞の運動性に関与することを示した。 4.Srcファミリー遺伝子lynを欠損するマウスでは末梢B細胞が減少しかつ自己免疫疾患を発症することを示した。このことはLynが抗原刺激に伴うB細胞の増殖と免疫寛容に関わることを指摘している。 5.NMDA受容体やAMPA受容体にそれぞれSrcファミリーキナーゼFynとLynが会合することを見い出し、これらキナーゼがシナプスの可塑性に関与することを示唆した。 6.チロシンキナーゼと共に細胞内チロシンりん酸化反応に関与するチロシンフォスファターゼを2種(BypとTyp)新規に見い出した。それぞれの発現様式と会合蛋白質の解析から、Bypが脳でFynと共同的に機能していること、またTypが精細胞の分化増殖に関与することが示唆された。 7.Bc13蛋白質がAb1チロシンキナーゼを活性化することを示し、染色体転座t(14;19)によるBc13の発現増大がAb1を介して白血病の発症を導くことを示唆した。

研究成果
(30件)

すべてその他

すべて文献書誌 (30件)

[文献書誌] 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.Accd.Sci.USA.92. 4432-4436 (1995)
[文献書誌] Takahashi,T.: "Human A-myb gene encodes a transcriptional activator containing the negative regulatory domains." FEBS Letters. 358. 89-96 (1995)
[文献書誌] Watanabe,N.: "Expression of C-terminal src Kinase in Human colorectal Cancer" Jpn.J.Clin.Oncol.25. 5-6 (1995)
[文献書誌] Shiota,M.: "Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK,a distinct clonocopatologic entity." Blood. 86. 1954-1960 (1995)
[文献書誌] Ilic,D.: "Focal Adhesion Kinase is noto Essential for in vitro and in vivo Differentiation of ES Cells." Biocem.and Biophys.Res.Comm.209. 300-309 (1995)
[文献書誌] Ilic,D.: "Reduced cell motility and enhanced focal adbesion contact formation in cells from FAK-deficient mice." Nature. 377. 539-544 (1995)
[文献書誌] Hohashi,N.: "The protein-tyrosine kinase Fyn activates transcription from the human immunodeficiency virus(HIV)promoter via activation of NFkB-like DNA-Binding proteins." Int′l Immunol.7. 1851-1859 (1996)
[文献書誌] Furuta,Y.: "Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase,FAK." Oncogene. (in press). (1996)
[文献書誌] Tezuka,T.: "Physical and functional association of the cbl proto-oncogene product with a Src-family protein tyrosine kinase,p53/56^<lyn>,in the B cell antigen receptor-mediated signaling." J.Exp.Med.(in press). (1996)
[文献書誌] Kanazawa,S.: "Integrin-Stimulation Decreases Tyrosine Phosphorylation and Activity of Focal Adbesion Kinase in Thymocytes." Biochem.Biophys.Res.Chem.(in press). (1996)
[文献書誌] Onoda,M.: "ErB-2 Expression is Correlated with Poor Prognosis in Osteosarcomas." Cancer. 77. 71-78 (1996)
[文献書誌] Mogi,A.: "Possible role of protein kinase C in the regulation of intracellular stability of focal adbesion kinase in mouse 3T3 cells." FEBS Letters. 373. 135-140 (1995)
[文献書誌] Li,B.Q.: "The catalytic activity of mSos guanine nucleotide exchanger is activated by Fyn TPK and T-cell antigen receptor in T-Cells." Proc.Natl.Acad.Sci.USA. (in press). (1996)
[文献書誌] Satake,H.: "Cupricion blocks NFkB activation through inhibiting the signal-induced phosphorylation of IkBa." Biochem.Biophys.Res.Commun.(in press). (1996)
[文献書誌] Fujimoto,J.: "Charcterization of the transforming activity of p80,a hyperphosphorylated protein in a Ki-1 lymphoma cell line with t(2;5)" Proc.Natl.Acad.Sci.USA. (in press). (1996)
[文献書誌] Yasunaga,M.: "Involvement of Fyn Tyrosine Kinase in Progression of Cytokinesis of B Lymphocyte Progenitor." J.Cell Biol.(in press). (1996)
[文献書誌] Kanazawa,S.: "p59^<fyn>-p125^<FAK>cooperation in development of CD4+CD8+thymocytes." Blood. (in press). (1996)
[文献書誌] Kuramochi,S.: "Molecular cloning and characterization of Byp,a murine receptor-type tyrosine phosphatase similar to human DEP-1." FEBS Letters. 378. 7-14 (1996)
[文献書誌] Yasukawa,T.: "Increase of Solubility of Foreign Proteins in Escherichia coli by Coproduction of the Bacterial Thioredoxin." J.Biol.Chem.270. 1-4 (1995)
[文献書誌] Otsuka,M.: "Novel Zinc Chelatocs with Dual Activity in the Inhibition of the kB Site-Binding Proteins HIV-EP1 and NF-kB." J.Med.Chem.38. 3264-3270 (1995)
[文献書誌] Matsuda,S.: "Tob,a novel protein that interacts with p185^<erbB2>,is associated with anti-proliferative activity." Oncogene. (in press). (1996)
[文献書誌] Nishizumi,H.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient Mice." Immunity. 3. 549-560 (1995)
[文献書誌] Tokai,N.: "Kid,a novel kinesin-like DNA binding protein,is colocalized with the chromosomes during mitosis." EMBO J.(in press). (1996)
[文献書誌] Ishida,T.: "CD40 signaling-mediated induction of Bcl-xL,Cdk4 and Cdk6:Implication of their co-operation in selective B cell growth." J.Immunology. (in press). (1996)
[文献書誌] Fusaki,N.: "Physical and Frunctional Interactions of Proein Tyrosine Kinases,p59^<tyn>and ZAP-70,in T Cell Signaling." J.Immunol.(in press). (1996)
[文献書誌] Suzuki,K.: "Molecular cloning of cDNA encoding the Xenopus homologue of mammalian RelB." Nucleic Acids Res.23. 4664-4669 (1995)
[文献書誌] Shiio,Y.: "Acitivation of the retinoblastoma gene expession by Bcl-3:Implication for muscle cell differenctiation" Oncogene. (in press). (1996)
[文献書誌] Kondo,M.: "Molecular cloning of Xenopus activation type 1 receptor and the analysis of its expression during embryogenesis" Biochem.Biophys.Res.Commun.(in press). (1996)
[文献書誌] Yamamoto,T.: "Superfamilies of Protooncogenes:Homology Cloning and Characterization of Related Members." Methods in Enzymology(eds.Vogt and Verma)Academic Press., 15 (1995)
[文献書誌] Yamamoto,T.: "Molecular biology of cancer:Oncogenes and tumorsuppressor genes." Molecular Biology in Clinical Oncology and Hematology, 15 (1995)

1995 年度 実績報告書

がん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] 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.Accd.Sci.USA.92. 4432-4436 (1995)

[文献書誌] Takahashi,T.: "Human A-myb gene encodes a transcriptional activator containing the negative regulatory domains." FEBS Letters. 358. 89-96 (1995)

[文献書誌] Watanabe,N.: "Expression of C-terminal src Kinase in Human colorectal Cancer" Jpn.J.Clin.Oncol.25. 5-6 (1995)

[文献書誌] Shiota,M.: "Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK,a distinct clonocopatologic entity." Blood. 86. 1954-1960 (1995)

[文献書誌] Ilic,D.: "Focal Adhesion Kinase is noto Essential for in vitro and in vivo Differentiation of ES Cells." Biocem.and Biophys.Res.Comm.209. 300-309 (1995)

[文献書誌] Ilic,D.: "Reduced cell motility and enhanced focal adbesion contact formation in cells from FAK-deficient mice." Nature. 377. 539-544 (1995)

[文献書誌] Hohashi,N.: "The protein-tyrosine kinase Fyn activates transcription from the human immunodeficiency virus(HIV)promoter via activation of NFkB-like DNA-Binding proteins." Int′l Immunol.7. 1851-1859 (1996)

[文献書誌] Furuta,Y.: "Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase,FAK." Oncogene. (in press). (1996)

[文献書誌] Tezuka,T.: "Physical and functional association of the cbl proto-oncogene product with a Src-family protein tyrosine kinase,p53/56^<lyn>,in the B cell antigen receptor-mediated signaling." J.Exp.Med.(in press). (1996)

[文献書誌] Kanazawa,S.: "Integrin-Stimulation Decreases Tyrosine Phosphorylation and Activity of Focal Adbesion Kinase in Thymocytes." Biochem.Biophys.Res.Chem.(in press). (1996)

[文献書誌] Onoda,M.: "ErB-2 Expression is Correlated with Poor Prognosis in Osteosarcomas." Cancer. 77. 71-78 (1996)

[文献書誌] Mogi,A.: "Possible role of protein kinase C in the regulation of intracellular stability of focal adbesion kinase in mouse 3T3 cells." FEBS Letters. 373. 135-140 (1995)

[文献書誌] Li,B.Q.: "The catalytic activity of mSos guanine nucleotide exchanger is activated by Fyn TPK and T-cell antigen receptor in T-Cells." Proc.Natl.Acad.Sci.USA. (in press). (1996)

[文献書誌] Satake,H.: "Cupricion blocks NFkB activation through inhibiting the signal-induced phosphorylation of IkBa." Biochem.Biophys.Res.Commun.(in press). (1996)

[文献書誌] Fujimoto,J.: "Charcterization of the transforming activity of p80,a hyperphosphorylated protein in a Ki-1 lymphoma cell line with t(2;5)" Proc.Natl.Acad.Sci.USA. (in press). (1996)

[文献書誌] Yasunaga,M.: "Involvement of Fyn Tyrosine Kinase in Progression of Cytokinesis of B Lymphocyte Progenitor." J.Cell Biol.(in press). (1996)

[文献書誌] Kanazawa,S.: "p59^<fyn>-p125^<FAK>cooperation in development of CD4+CD8+thymocytes." Blood. (in press). (1996)

[文献書誌] Kuramochi,S.: "Molecular cloning and characterization of Byp,a murine receptor-type tyrosine phosphatase similar to human DEP-1." FEBS Letters. 378. 7-14 (1996)

[文献書誌] Yasukawa,T.: "Increase of Solubility of Foreign Proteins in Escherichia coli by Coproduction of the Bacterial Thioredoxin." J.Biol.Chem.270. 1-4 (1995)

[文献書誌] Otsuka,M.: "Novel Zinc Chelatocs with Dual Activity in the Inhibition of the kB Site-Binding Proteins HIV-EP1 and NF-kB." J.Med.Chem.38. 3264-3270 (1995)

[文献書誌] Matsuda,S.: "Tob,a novel protein that interacts with p185^<erbB2>,is associated with anti-proliferative activity." Oncogene. (in press). (1996)

[文献書誌] Nishizumi,H.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient Mice." Immunity. 3. 549-560 (1995)

[文献書誌] Tokai,N.: "Kid,a novel kinesin-like DNA binding protein,is colocalized with the chromosomes during mitosis." EMBO J.(in press). (1996)

[文献書誌] Ishida,T.: "CD40 signaling-mediated induction of Bcl-xL,Cdk4 and Cdk6:Implication of their co-operation in selective B cell growth." J.Immunology. (in press). (1996)

[文献書誌] Fusaki,N.: "Physical and Frunctional Interactions of Proein Tyrosine Kinases,p59^<tyn>and ZAP-70,in T Cell Signaling." J.Immunol.(in press). (1996)

[文献書誌] Suzuki,K.: "Molecular cloning of cDNA encoding the Xenopus homologue of mammalian RelB." Nucleic Acids Res.23. 4664-4669 (1995)

[文献書誌] Shiio,Y.: "Acitivation of the retinoblastoma gene expession by Bcl-3:Implication for muscle cell differenctiation" Oncogene. (in press). (1996)

[文献書誌] Kondo,M.: "Molecular cloning of Xenopus activation type 1 receptor and the analysis of its expression during embryogenesis" Biochem.Biophys.Res.Commun.(in press). (1996)

[文献書誌] Yamamoto,T.: "Superfamilies of Protooncogenes:Homology Cloning and Characterization of Related Members." Methods in Enzymology(eds.Vogt and Verma)Academic Press., 15 (1995)

[文献書誌] Yamamoto,T.: "Molecular biology of cancer:Oncogenes and tumorsuppressor genes." Molecular Biology in Clinical Oncology and Hematology, 15 (1995)

1995 年度実績報告書

山本雅東京大学, 医科学研究所, 教授 (40134621)