1994 Fiscal Year Annual Research Report

癌遺伝子産物の生理機能に基づく発癌機構の解析

Research Project

Project/Area Number	06283203
Research Category	Grant-in-Aid for Scientific Research on Priority Areas
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)	椎尾譲東京大学, 医科学研究所, 学振特別研究員梅森久視東京大学, 医科学研究所, 助手 (20242117) 松田覚東京大学, 医科学研究所, 助手 (50242110)
Keywords	癌遺伝子 / Tのシンキナーゼ / シグナル伝達 / リンパ球活性反応 / 中枢神経系 / リンパ腫 / 増殖因子受容体 / 遺伝子欠損マウス
Research Abstract	1.受容体型チロシンキナーゼErbB-2からのシグナル伝達に関わる分子としてTob蛋白質を見い出した。Tobは通常細胞核に局在し細胞増殖を抑制するが、ErbB-2過剰発現細胞ではErbB-2と相互作用して細胞質に分布し、増殖抑制活性を失う。 2.免疫系細胞においてSrc型チロシンキナーゼLynやFynはSyk,ZAP-70と相互作用し、HSI蛋白質をリン酸化することを見い出した。非リン酸化型HS1は細胞質に存在するが、チロシンリン酸化されることにより核へ移行しうる。更に我々は酵母の“Two-hybrid system"を利用し、LynのSH3ドメインと相互作用する分子としてp120^<cbl>を見い出した。p120^<cbl>はB細胞抗原受容体刺激によって一過性にチロシンリン酸化レベルが亢進する。また、lyn遺伝子欠損マウスを作成し解析を進めている。 3.中枢神経系で、MAGと相互作用してミエリン形成に関わるFynからのシグナルが、MBP遺伝子のプロモーターに作用することを示した。また、アデノウイルスベクターを用いてlyn発現ウイルスを作成し、これを培養脳細胞に感染させることにより、Lynによってリン酸化される蛋白質の一つとしてグルタミン酸受容体を見い出した。 4.Ki-1リンパ腫で見られるt(2;5)転座により第2染色体上のチロシンキナーゼ遺伝子alkが、第5染色体上のヌクレオフォスミン(NPM)遺伝子と融合しNPM-Alkキメラ蛋白質が作られることを示した。このキメラ蛋白質はNIH3T3細胞を癌化する。この癌化活性にはキナーゼドメインのみならずNPMドメインの存在が必須である。 5.fak欠損マウスを作成し、fak^<-1->細胞が運動能に欠損があり、マウスは中胚葉由来細胞の異常から8日胚で胚死することを見い出した。

Research Products
(17 results)

All Other

All Publications (17 results)

[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)
[Publications] Shiota,M.,: "Hyperphosphorylation of a novel 80-kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line,AMS3." Oncogene. 9. 1567-1574 (1994)
[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)
[Publications] Nagata,K.,: "Solution structure of the epidermal growth factor-like domain of heregulin-a,a ligand for p180^<erbB-4>." EMBO J. 13. 3513-3517 (1994)
[Publications] Katagiri,K.,: "Activation of ras and Fformation of GAP complex during TPA-induced monocytic differentiation of HL-60 cells." Blood,. 84. 1780-1789 (1994)
[Publications] Kurosaki,T.: "Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling." J,Exp.Med.17. 1725-1729 (1994)
[Publications] Fujita,K.,: "Enhancement of T cell receptor signaling of tumor-infiltrating lymphocytes by retrovirally mediated fyn gene transduction.Jpn." J.Cancer Res.85. 1073-1079 (1994)
[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),

1994 Fiscal Year Annual Research Report

癌遺伝子産物の生理機能に基づく発癌機構の解析

Principal Investigator

山本 雅 東京大学, 医科学研究所, 教授 (40134621)

Research Products

[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)

[Publications] Shiota,M.,: "Hyperphosphorylation of a novel 80-kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line,AMS3." Oncogene. 9. 1567-1574 (1994)

[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)

[Publications] Nagata,K.,: "Solution structure of the epidermal growth factor-like domain of heregulin-a,a ligand for p180^<erbB-4>." EMBO J. 13. 3513-3517 (1994)

[Publications] Katagiri,K.,: "Activation of ras and Fformation of GAP complex during TPA-induced monocytic differentiation of HL-60 cells." Blood,. 84. 1780-1789 (1994)

[Publications] Kurosaki,T.: "Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling." J,Exp.Med.17. 1725-1729 (1994)

[Publications] Fujita,K.,: "Enhancement of T cell receptor signaling of tumor-infiltrating lymphocytes by retrovirally mediated fyn gene transduction.Jpn." J.Cancer Res.85. 1073-1079 (1994)

[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),

山本雅東京大学, 医科学研究所, 教授 (40134621)