1991 年度実績報告書

がん遺伝子の機能解析

研究課題

研究課題/領域番号	03258203
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	豊島久真男大阪大学, 微生物病研究所, 教授 (90029760) 松田覚東京大学, 医科学研究所, 学振研究員仙波憲太郎東京大学, 医科学研究所, 助手 (70206663)
キーワード	チロシンキナ-ゼ / シグナル伝達 / リンパ球活性化 / 乳癌 / 増殖因子 / 転写調節 / トランスジェニックマウス
研究概要	リンパ球の抗原受容体と物理的に会合しているLynやFynが、抗原受容体を介するシグナル伝達反応に於て機能していることを示した。そして、Lynからのシグナル伝達系には、分子量約70,000のチロシンリン酸化された蛋白質やPIー3キナ-ゼが関わっていること、また、FynからのシグナルがSH2とCD3ζ鎖の相互作用により下流に伝えられることを示唆した。さらに、脳においてFynは胚ならびに生直後そして成体の全てで、海馬等の神経細胞で発現している事を示した。更に、免疫グロブリン遺伝子エンハンサ-支配下のlynならびにfyncDNAをtransgeneとして有するマウスを作成し、B細胞の機能・分化についての解析を進めている。さらに、gene targeting法により、fyn遺伝子を欠損するマウスを共同研究で得ているし、lyn遺伝子についても進行中である。Yes蛋白質については、アミノ末端近傍で細胞周期依存的にリン酸化されることを見いだし、その意義について検討中である。ErbBー2蛋白質については、子牛血清中に見いだした特異的なキナ-ゼ活性促進因子の精製を進め、アルファフェトプロテインに富む画分にその活性をが存在することを見いだした。さらに数種のステロイドホルモンがErbBー2蛋白質に直接結合して、そのキナ-ゼ活性を亢進させること、そしてErbBー2蛋白質の標的蛋白質としてPIー3キナ-ゼと蛋白質とキナ-ゼ活性を有する分子を予備的に見いだしている。遺伝子発現調節機構の解析に関しては、lyn遺伝子とcーerbBー2遺伝子について進展があった。まずp40^<tax>によりlyn遺伝子プロモ-タ-が活性化されることを明かにすると共にそのプロモ-タ-領域の詳細な解析を行なった。cーerbBー2プロモ-タ-に関しては、乳癌細胞株での転写活性上昇に関わる配列に結合する転写因子の候補を得ている。

研究成果

(22件)

すべてその他

すべて文献書誌 (22件)

[文献書誌] Masatugu Moriyama: "Expression of the c‐erbB‐2 gene product in urinary bladder cancer" J.Urology. 145. 423-427 (1991)
[文献書誌] Yuji Yamanashi: "Associations of B cell antigen receptor and protein‐tyrosine kinase p56^<lyn>" Science. 251. 192-194 (1991)
[文献書誌] Tsuneo Saga: "Imaging of c‐erbB‐2 gene product:in vivo application of anti‐c‐erbB‐2 protein antibody" Cancer Res.51. 990-994 (1991)
[文献書誌] Koko Katagiri: "Expression of src family genes during monocytic differentiation of HL 60 cells" J.Immunol.146. 701-709 (1991)
[文献書誌] Komei Sugawara: "Distribution of c‐yes‐1 gene product in various cells and tissues" Br.J.Cancer. 63. 508-513 (1991)
[文献書誌] Kazuyoshi Azuma: "Purification and characterization of rat liver membrane tyrosine kinase,the possible protooncogene c‐yes product,p60^<c‐yes>" J.Biol.Chem.266. 4831-4839 (1991)
[文献書誌] Tetsu Akiyama: "The transforming potential of the c‐erbB‐2 protein is regulated by its autophosphorylation at the carboxyterminal domain" Mol.Cell.Biol.11. 833-842 (1991)
[文献書誌] Akiko Fujimoto: "Stimulation of the TPA‐response element by the activated c‐erbB‐2 protein is partly mediated by protein kinase C" Biochem.Biophys.Res.Commun.178. 724-732 (1991)
[文献書誌] Yumiko Matsuzawa: "Characterization of the promoter region of the yes‐protooncogene" Oncogene. 6. 1561-1568 (1991)
[文献書誌] Sachiko Tsukita: "The c‐yes and lyn tyrosine kinases are specifically enriched in cell‐cell adherence junctions" J.Cell Biol.113. 867-879 (1991)
[文献書誌] Koichi Rikimaru: "Gene amplification of epidermal growth factor receptor in squamous cell carcinoma of head and neck cancer" Br.J.Cancer.
[文献書誌] Yuji Yamanashi: "Differential responses of p56^<lyn> and p53^<lyn> products of alternatively spliced lyn mRNA,upon stimulation of B cell antigen receptor" Cell Regulation. 2. 979-987 (1991)
[文献書誌] Masato Okada: "CSK:A protein‐tyrosine kinase involved in regulation of src‐family kinases" J.Biol.Chem.
[文献書誌] Junichiro Mizuguchi: "Tyrosine protein kinase is involved in anti‐IgM‐mediated signalling in Bal17 B lymphoma" J.Immunol.
[文献書誌] Kaoru Morishita: "Expression and characterization of biologically active v‐erbB protein using a baculovirus system" J.J.Cancer Res. 83. 52-60 (1992)
[文献書誌] Shigeo Koyasu: "Phosphorylation of multiple CD3ζ tyrosine residues lends to formation of pp21 in vitro:Structural changes upon T cell receptor stimulation" J.Biol.Chem.
[文献書誌] Yuji Yamanashi: "Activation of Src‐like protein‐tyrosine kinase Lyn and Lyn‐associated PI‐3 kinase upon B cell antigen receptor‐mediated signalling" Proc.Natl.Acad.Sci.USA. 89. 1118-1122 (1992)
[文献書誌] Rujiao Shan: "Detection of the ligand activity for the c‐erbB‐2 protein in calf serum" J.J.Cancer Res.83. 15-19 (1992)
[文献書誌] Budsaba Wongsasant: "Active c‐erbB‐2 induces short‐term growth of FDC‐P2 cells after IL‐3 depletion" Biochem.Biophys.Res.Commun.
[文献書誌] Yasunori Kadowaki: "Ear3/Coup‐TF binds most tightly to a response element with tandem repeat separated by one nucleotide" Biochem.Biophys.Res.Commun.
[文献書誌] Koko Katagiri: "Modulation of monocytic differentiation of HL‐60 cells by inhibitors of protein tyrosine kinases" Cell Immunol.
[文献書誌] Takuya Katagiri: "Action of murine autoimmune‐accelerating genes,lpr and Yaa:Enhanced activity of src family tyrosine kinases in abnormal T and B cells" Molecular Approaches to the Study and Treatment of Human Diseases,T.O.Yoshida and J.M.Wilson,eds.Elsevier Amsterdam,

1991 年度 実績報告書

がん遺伝子の機能解析

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] Masatugu Moriyama: "Expression of the c‐erbB‐2 gene product in urinary bladder cancer" J.Urology. 145. 423-427 (1991)

[文献書誌] Yuji Yamanashi: "Associations of B cell antigen receptor and protein‐tyrosine kinase p56^<lyn>" Science. 251. 192-194 (1991)

[文献書誌] Tsuneo Saga: "Imaging of c‐erbB‐2 gene product:in vivo application of anti‐c‐erbB‐2 protein antibody" Cancer Res.51. 990-994 (1991)

[文献書誌] Koko Katagiri: "Expression of src family genes during monocytic differentiation of HL 60 cells" J.Immunol.146. 701-709 (1991)

[文献書誌] Komei Sugawara: "Distribution of c‐yes‐1 gene product in various cells and tissues" Br.J.Cancer. 63. 508-513 (1991)

[文献書誌] Kazuyoshi Azuma: "Purification and characterization of rat liver membrane tyrosine kinase,the possible protooncogene c‐yes product,p60^<c‐yes>" J.Biol.Chem.266. 4831-4839 (1991)

[文献書誌] Tetsu Akiyama: "The transforming potential of the c‐erbB‐2 protein is regulated by its autophosphorylation at the carboxyterminal domain" Mol.Cell.Biol.11. 833-842 (1991)

[文献書誌] Akiko Fujimoto: "Stimulation of the TPA‐response element by the activated c‐erbB‐2 protein is partly mediated by protein kinase C" Biochem.Biophys.Res.Commun.178. 724-732 (1991)

[文献書誌] Yumiko Matsuzawa: "Characterization of the promoter region of the yes‐protooncogene" Oncogene. 6. 1561-1568 (1991)

[文献書誌] Sachiko Tsukita: "The c‐yes and lyn tyrosine kinases are specifically enriched in cell‐cell adherence junctions" J.Cell Biol.113. 867-879 (1991)

[文献書誌] Koichi Rikimaru: "Gene amplification of epidermal growth factor receptor in squamous cell carcinoma of head and neck cancer" Br.J.Cancer.

[文献書誌] Yuji Yamanashi: "Differential responses of p56^<lyn> and p53^<lyn> products of alternatively spliced lyn mRNA,upon stimulation of B cell antigen receptor" Cell Regulation. 2. 979-987 (1991)

[文献書誌] Masato Okada: "CSK:A protein‐tyrosine kinase involved in regulation of src‐family kinases" J.Biol.Chem.

[文献書誌] Junichiro Mizuguchi: "Tyrosine protein kinase is involved in anti‐IgM‐mediated signalling in Bal17 B lymphoma" J.Immunol.

[文献書誌] Kaoru Morishita: "Expression and characterization of biologically active v‐erbB protein using a baculovirus system" J.J.Cancer Res. 83. 52-60 (1992)

[文献書誌] Shigeo Koyasu: "Phosphorylation of multiple CD3ζ tyrosine residues lends to formation of pp21 in vitro:Structural changes upon T cell receptor stimulation" J.Biol.Chem.

[文献書誌] Yuji Yamanashi: "Activation of Src‐like protein‐tyrosine kinase Lyn and Lyn‐associated PI‐3 kinase upon B cell antigen receptor‐mediated signalling" Proc.Natl.Acad.Sci.USA. 89. 1118-1122 (1992)

[文献書誌] Rujiao Shan: "Detection of the ligand activity for the c‐erbB‐2 protein in calf serum" J.J.Cancer Res.83. 15-19 (1992)

[文献書誌] Budsaba Wongsasant: "Active c‐erbB‐2 induces short‐term growth of FDC‐P2 cells after IL‐3 depletion" Biochem.Biophys.Res.Commun.

[文献書誌] Yasunori Kadowaki: "Ear3/Coup‐TF binds most tightly to a response element with tandem repeat separated by one nucleotide" Biochem.Biophys.Res.Commun.

[文献書誌] Koko Katagiri: "Modulation of monocytic differentiation of HL‐60 cells by inhibitors of protein tyrosine kinases" Cell Immunol.

[文献書誌] Takuya Katagiri: "Action of murine autoimmune‐accelerating genes,lpr and Yaa:Enhanced activity of src family tyrosine kinases in abnormal T and B cells" Molecular Approaches to the Study and Treatment of Human Diseases,T.O.Yoshida and J.M.Wilson,eds.Elsevier Amsterdam,

1991 年度実績報告書

山本雅東京大学, 医科学研究所, 教授 (40134621)