1992 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	04253203
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, 教務職員 (20242117) 松田覚東京大学, 医科学研究所, 助手 (50242110)
キーワード	癌遺伝子 / チロシンキナーゼ / シグナル伝達 / リンパ球活性化反応 / 中枢神経系 / 乳癌 / 増殖因子受容体 / スチロイドホルモン受容体
研究概要	1.チロシンキナーゼ活性の異常亢進が癌の発症や進展に深く関わっているという知見が畜積している。我々はその分子機構を解明することを目的として、チロシンキナーゼ群癌原遺伝子の正常細胞における機能解析を進めてきた。今年度は主に(1)Bリンパ球の抗原受容体刺激に伴って活性化されるLynキナーゼの標的候補の一つとして転写因子様の配列helix-turn-helixを分子の中央部に、そしてSH3配列を分子のC末端に在するp75_<HS1>を同定した。また(2)Fynのキナーゼが活性亢進がc-fosプロモーターやIL-2遺伝子プロモーターに正に作用しているが、Csk蛋白質がFyNの528Tyrをリン酸化してT-Fynキナーゼのこのような作用を抑制すること、(3)FynやLynがCskと物理的に相互作用していることを示した。一方(4)中枢神経系に於いてはFynが海馬等に存在する神経細胞のみならず、乏突起細胞でも発現していて、伴ミエリン糖蛋白質MAGと会合していることを明らかにし、更にミエリン形成に関与している可能性を示唆する知見を得た。(5)受容体型c-ErbB-2蛋白質についてはエストロゲンがc-ErbB-2に結合し、c-ErbB-2キナーゼ活性を促進するなどのリガンド様活性を示すと指摘した。また、(6)癌でのcerbB-2発現異常亢進機構を明らかにする目的でc-erbB-2プロモーター領域に結合する蛋白質を探索し、2種の蛋白質に対するcDNAクローンを得て解析を進めている。 2.erbAファミリー癌遺伝子ear-3の産物が(1)DRIやTRE等のエンハンサー配列に結合すること、また(2)特定遺伝子の転写活性を結合部位依存的に正にも負にも制御することを示した。

研究成果
(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Koichi Rikimura: "Gene amplification of epidermal growth factor receptor in sqamous cell caricinoma of head and neck cancer." Br.J.Cancer. 14. 8-13 (1992)
[文献書誌] Junichiro Mizuguchi: "Tyrosine protein kinase is involved in anti-IgM-mediated signalling in Bal17 B lymphoma cells." J.Immunol.148. 689-694 (1992)
[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 CD3z tyrosine residues lends to formation of pp21 in vitro:Structural changes upon T cell receptor stimulation." J.Biol.Chem.267. 3375-3381 (1992)
[文献書誌] Yuji Yamanashi: "Activation of Src-like protein-tyrosine kinase Lyn and Lyn assciated OI-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] Yasunori Kadowaki: "Ear3/Coup-TF binds most tightly to a response element with tandem repeat separated by one nucleotide." Biochem.Biophys.Res.Commun.183. 492-498 (1992)
[文献書誌] Koko Katagiri: "Modulation of monocytic differentiation of HL60 cells by inhibitors of protein-tyrosine kinases." Cell Immunol.140. 282-294 (1992)
[文献書誌] Yuzuru Shiio: "Negative regulation of Rb expression by the p53 gene product." Proc.Natl.Acad.Sci.USA. 89. 5206-5210 (1992)
[文献書誌] Hisashi Umemori: "Specific expression of antigen receptor-associated tyrosine kinases,Fyn and Lyn,in the central nervous system." Mol.Brain Res.16. 303-310 (1992)
[文献書誌] Fumiaki Uchiumi: "Characterization of the promoter tegion of the src-family gene lynand its trans-activation by HTLV-I encoded p40tax." Mol.Cell.Biol.12. 3784-3795 (1992)
[文献書誌] Marius Sudol: "Novel yes-related kinase,Yrk,is expressed at elevated levels in neural and hematopoietic tissues." Oncogene.
[文献書誌] Makoto Hosono: "Construction of Immunoradiometric assay for cirulating c-erbB-2 protooncogene product in advanced breast cancer patients." Jpn.J.Cancer Res.
[文献書誌] Masahiko Kinosaki: "Intracellular localization of UDP-glucuronosyltransferase expressed from the transfected cDNA in cultured cells." Cell Structure and Function.
[文献書誌] Takaomi Ishida: "Molecular cloning and characterization of the promoter region of the human c-erbAα gene." Biochem.Biophys.Res.Commun.
[文献書誌] Yuji Yamanashi: "Identification of HS1 protein as a major substrate of protein-tyrosine kinase(s) upon B cell antigen receptor-mediated signaling." Proc.Natl.Acad.Sci,USA.
[文献書誌] Takahiro Miyauchi: "Purification and characterzation of the possible protooncogene fyn product,p59fyn,from rat brain patriculate fraction." J.Biochem.
[文献書誌] Koko Katagiri: "Tyrosine phosphorylation of tubulins during monocytic differentiation of HL-60 cells." J.Immunol.
[文献書誌] Tadashi Yamamoto: "Cancer Chemotherapy,Challenges for the Future" Excerpta Medica,Tokyo, 6 (1992)
[文献書誌] Takuya Katagiri: "Molecular Approaches to the Study and Treatment of Human Diseases" Elsevier,Amsterdam, 8 (1992)
[文献書誌] Tadashi Yamamoto: "Immunological Reviews:The B-cell Antigen Receptor Complex" Munksgaard,Copenhagen, 20 (1993)

1992 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] Koichi Rikimura: "Gene amplification of epidermal growth factor receptor in sqamous cell caricinoma of head and neck cancer." Br.J.Cancer. 14. 8-13 (1992)

[文献書誌] Junichiro Mizuguchi: "Tyrosine protein kinase is involved in anti-IgM-mediated signalling in Bal17 B lymphoma cells." J.Immunol.148. 689-694 (1992)

[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 CD3z tyrosine residues lends to formation of pp21 in vitro:Structural changes upon T cell receptor stimulation." J.Biol.Chem.267. 3375-3381 (1992)

[文献書誌] Yuji Yamanashi: "Activation of Src-like protein-tyrosine kinase Lyn and Lyn assciated OI-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] Yasunori Kadowaki: "Ear3/Coup-TF binds most tightly to a response element with tandem repeat separated by one nucleotide." Biochem.Biophys.Res.Commun.183. 492-498 (1992)

[文献書誌] Koko Katagiri: "Modulation of monocytic differentiation of HL60 cells by inhibitors of protein-tyrosine kinases." Cell Immunol.140. 282-294 (1992)

[文献書誌] Yuzuru Shiio: "Negative regulation of Rb expression by the p53 gene product." Proc.Natl.Acad.Sci.USA. 89. 5206-5210 (1992)

[文献書誌] Hisashi Umemori: "Specific expression of antigen receptor-associated tyrosine kinases,Fyn and Lyn,in the central nervous system." Mol.Brain Res.16. 303-310 (1992)

[文献書誌] Fumiaki Uchiumi: "Characterization of the promoter tegion of the src-family gene lynand its trans-activation by HTLV-I encoded p40tax." Mol.Cell.Biol.12. 3784-3795 (1992)

[文献書誌] Marius Sudol: "Novel yes-related kinase,Yrk,is expressed at elevated levels in neural and hematopoietic tissues." Oncogene.

[文献書誌] Makoto Hosono: "Construction of Immunoradiometric assay for cirulating c-erbB-2 protooncogene product in advanced breast cancer patients." Jpn.J.Cancer Res.

[文献書誌] Masahiko Kinosaki: "Intracellular localization of UDP-glucuronosyltransferase expressed from the transfected cDNA in cultured cells." Cell Structure and Function.

[文献書誌] Takaomi Ishida: "Molecular cloning and characterization of the promoter region of the human c-erbAα gene." Biochem.Biophys.Res.Commun.

[文献書誌] Yuji Yamanashi: "Identification of HS1 protein as a major substrate of protein-tyrosine kinase(s) upon B cell antigen receptor-mediated signaling." Proc.Natl.Acad.Sci,USA.

[文献書誌] Takahiro Miyauchi: "Purification and characterzation of the possible protooncogene fyn product,p59fyn,from rat brain patriculate fraction." J.Biochem.

[文献書誌] Koko Katagiri: "Tyrosine phosphorylation of tubulins during monocytic differentiation of HL-60 cells." J.Immunol.

[文献書誌] Tadashi Yamamoto: "Cancer Chemotherapy,Challenges for the Future" Excerpta Medica,Tokyo, 6 (1992)

[文献書誌] Takuya Katagiri: "Molecular Approaches to the Study and Treatment of Human Diseases" Elsevier,Amsterdam, 8 (1992)

[文献書誌] Tadashi Yamamoto: "Immunological Reviews:The B-cell Antigen Receptor Complex" Munksgaard,Copenhagen, 20 (1993)

1992 年度実績報告書

山本雅東京大学, 医科学研究所, 教授 (40134621)