1996 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 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)	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	チロシンキナーゼ / チロシンフォスファターゼ / 細胞癌化 / シグナル伝達 / 細胞周期 / リンパ腫 / 免疫反応 / シナプス可塑性
Research Abstract	チロシンりん酸化反応が関与する細胞がん化機構ならびに細胞増殖調節機構、およびSrc型チロシンキナーゼが免疫系・神経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 染色体転座によって活性化され、Ki-1リンパ腫発症の主因となっているp80alkキナーゼについて、その正常型の機能解析を進めた。正常ALKは220kDaの受容体型糖蛋白質であり、中枢神経系に特異的に発現していることが明らかとなった。したがって、Ki-1リンパ腫は異所性のALK活性によって引き起こされていると考えられる。 2 乳癌等で高発現するErbB2チロシンキナーゼと相互作用するTob蛋白質の解析を進めた。その結果、Tobは分子の中央部分でリン酸化される可能性が指摘され、またその部分でErbB2と相互作用することが示唆された。TobならびにTobファミリーの一員であるTob4蛋白質が転写制御因子として見い出されたCaf-1蛋白質と相互作用すること、またCaf-1が細胞周期制御蛋白質と相互作用することを見い出した。この結果は、受容体型チロシンキナーゼから細胞周期制御系へのシグナル伝達経路の存在を指摘するものである。 3 細胞接着ならびに細胞運動に関わるFAKチロシンキナーゼとFynチロシンキナーゼの相互作用を調べるためにFAKとFyn両遺伝子を共に欠損するマウスを作成し、そのようなマウスでは皮膚の形成異常が見られることを示した。またFAK欠損マウス繊維が細胞のv-Srcを導入しても形態的なトランスフォーメーションが見られないことを示し、v-Srcがん化反応における細胞形態の変化、即ち細胞骨格系への作用にFAKが関わることを示唆した。 4 Lyn欠損肥満細胞を用いて、LynチロシンキナーゼがFeε受容体を介するシグナル伝達系に関与していることを示した。しかしながらLynに代わってSrcチロシンキナーゼが働くことにより、Lyn欠損肥満細胞に於ても抗原刺激に伴う脱顆粒は誘導されることを示した。 5 NMDA受容体とFynの会合が、がん抑制遺伝子産物Dlgの類似体であるPSD95蛋白質によって促進されることを示した。このことはNMDA受容体がシナプス伝達以外の機能を果している可能性を指摘している。 6 我々が見い出した新規チロシンフォスファターゼTypがパキテン期精母細胞に特異的に発現していることを示し、Typが原数分裂過程に関わる可能性を指摘した。

Research Products

(21 results)

All Other

All Publications (21 results)

[Publications] Satomi Kuramochi: "Molecular cloning and characterization of Byp,a murine receptor-type tyrosine phosphatase similar to human DEP-1." FEBS Letters. 378. 7-14 (1996)
[Publications] Bao-qun Li: "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. 93. 1001-1005 (1996)
[Publications] Noriko Tokai: "Kid,a novel kinesin-like DNA binding protein,is colocalized with the chromosomes during mitosis." EMBO J.15. 457-467 (1996)
[Publications] Masanori Onda: "Erb B-2 expression is correlated with poor prognosis in osteosarcomas." Cancer. 77. 71-78 (1996)
[Publications] Noemi Fusaki: "Physical and functional interactions of protein tyrosine kinases,p59fyn and ZAP-70,in T cell signaling" J.Immunol.156. 1369-1377 (1996)
[Publications] Mariko Kondo: "Molecular cloning of Xenopus activin type I receptor and the analysis of its expression during embryogenesis" Biochem.Biophys.Res.Commun.218. 549-555 (1996)
[Publications] Satoru Matsuda: "Tob,a novel protein that interacts with p185erbB2,is associated with anti-proliferative activity." Oncogene. 12. 705-713 (1996)
[Publications] Tohru Tezuka: "Physical and functional association of the Cbl proto-oncogene product with a Src-family protein tyrosine kinase,p53/56lyn,in the B cell antigen receptor-mediated signaling." J.Exp.Med.183. 675-680 (1996)
[Publications] Yuzuru Shiio: "Activation of the retinoblastoma gene expression by Bcl-3:Impication for muscle cell differentiatior" Oncogene. 12. 1837-1845 (1996)
[Publications] Jiro Fujimoto: "Characterization 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. 93. 4181-4186 (1996)
[Publications] Dusko Ilic: "Impairment of mobility in endodermal cells by FAK deficiency." Exp.Cell Res.222. 298-303 (1996)
[Publications] Shingo Maruyama: "Physical and functional association of cortactin with Syk in human leukemic cell line K562" J.Biol.Chem.271. 6631-6635 (1996)
[Publications] Takaomi Ishida: "TRAF5,a novel tumor necrosis factor receptor-associated factor family protein,mediates CD40 signaling" Proc.Natl.Acad.Sci.USA.93. 9437-9442 (1996)
[Publications] Takaomi Ishida: "Identification of TRAF6,a novel TRAF protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region." J.Biol.Chem.271. 28745-28748 (1996)
[Publications] Tsutomu Aoki: "Theankyrin repeats but not the PEST-like sequences are required for signal dependent degradation of IκBα." Oncogene. 12. 1159-1164 (1996)
[Publications] Toshinori Iwahara: "Molecular characterization of ALK,a receptor tyrosine kinase expressed specifically in the nervous system" Oncogene. 14. 439-449 (1997)
[Publications] Hirofumi Nishizumi: "Impaired Ca2+ mobilization but not degranulation in Lyn deficient bone marrow-derived mast cells." J.Immunol.(in press).
[Publications] Dusko Ilic: "Focal adhesion kinase at the crossroads of signal transduction." J.Cell.Sci.(in press).
[Publications] Y.Matsuda: "Chromosomal mapping of the mouse and rat brt genes." Genomics. (in press).
[Publications] T.Saito: "Localization of ZAP-70,the gene for a T cell-specific protein tyrosine kinase, to mouse and rat chromosomes by fluorescence in situ hybridization and molecular genetic linkage analyses." Mammalian Genome. (in press).
[Publications] Yuji Yamanashi: "Role of tyrosine phosphorylation of HSI in B cell antigen receptor-medicated apoptosis." J.Exp.Med.(in press).

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

[Publications] Bao-qun Li: "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. 93. 1001-1005 (1996)

[Publications] Noriko Tokai: "Kid,a novel kinesin-like DNA binding protein,is colocalized with the chromosomes during mitosis." EMBO J.15. 457-467 (1996)

[Publications] Masanori Onda: "Erb B-2 expression is correlated with poor prognosis in osteosarcomas." Cancer. 77. 71-78 (1996)

[Publications] Noemi Fusaki: "Physical and functional interactions of protein tyrosine kinases,p59fyn and ZAP-70,in T cell signaling" J.Immunol.156. 1369-1377 (1996)

[Publications] Mariko Kondo: "Molecular cloning of Xenopus activin type I receptor and the analysis of its expression during embryogenesis" Biochem.Biophys.Res.Commun.218. 549-555 (1996)

[Publications] Satoru Matsuda: "Tob,a novel protein that interacts with p185erbB2,is associated with anti-proliferative activity." Oncogene. 12. 705-713 (1996)

[Publications] Tohru Tezuka: "Physical and functional association of the Cbl proto-oncogene product with a Src-family protein tyrosine kinase,p53/56lyn,in the B cell antigen receptor-mediated signaling." J.Exp.Med.183. 675-680 (1996)

[Publications] Yuzuru Shiio: "Activation of the retinoblastoma gene expression by Bcl-3:Impication for muscle cell differentiatior" Oncogene. 12. 1837-1845 (1996)

[Publications] Jiro Fujimoto: "Characterization 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. 93. 4181-4186 (1996)

[Publications] Dusko Ilic: "Impairment of mobility in endodermal cells by FAK deficiency." Exp.Cell Res.222. 298-303 (1996)

[Publications] Shingo Maruyama: "Physical and functional association of cortactin with Syk in human leukemic cell line K562" J.Biol.Chem.271. 6631-6635 (1996)

[Publications] Takaomi Ishida: "TRAF5,a novel tumor necrosis factor receptor-associated factor family protein,mediates CD40 signaling" Proc.Natl.Acad.Sci.USA.93. 9437-9442 (1996)

[Publications] Takaomi Ishida: "Identification of TRAF6,a novel TRAF protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region." J.Biol.Chem.271. 28745-28748 (1996)

[Publications] Tsutomu Aoki: "Theankyrin repeats but not the PEST-like sequences are required for signal dependent degradation of IκBα." Oncogene. 12. 1159-1164 (1996)

[Publications] Toshinori Iwahara: "Molecular characterization of ALK,a receptor tyrosine kinase expressed specifically in the nervous system" Oncogene. 14. 439-449 (1997)

[Publications] Hirofumi Nishizumi: "Impaired Ca2+ mobilization but not degranulation in Lyn deficient bone marrow-derived mast cells." J.Immunol.(in press).

[Publications] Dusko Ilic: "Focal adhesion kinase at the crossroads of signal transduction." J.Cell.Sci.(in press).

[Publications] Y.Matsuda: "Chromosomal mapping of the mouse and rat brt genes." Genomics. (in press).

[Publications] T.Saito: "Localization of ZAP-70,the gene for a T cell-specific protein tyrosine kinase, to mouse and rat chromosomes by fluorescence in situ hybridization and molecular genetic linkage analyses." Mammalian Genome. (in press).

[Publications] Yuji Yamanashi: "Role of tyrosine phosphorylation of HSI in B cell antigen receptor-medicated apoptosis." J.Exp.Med.(in press).

山本雅東京大学, 医科学研究所, 教授 (40134621)