1997 年度実績報告書

癌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
研究種目	重点領域研究
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	藤元次郎東京大学, 医科学研究所, 教務職員 (60282521) 梅森久視東京大学, 医科学研究所, 助手 (20242117) 松田覚名古屋大学, 医学部, 講師 (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 / Srcファミリー / 三量体G蛋白質 / 細胞周期 / Tobファミリー / リンパ腫 / リンパ球活性化
研究概要	癌細胞の増殖異常や正常細胞の増殖・分化の制御に関わるチロシンキナーゼとチロシンフォスファターゼの機能に関して以下の点を明らかにした。 1.Ki-1リンパ腫で活性化されている受容体型チロシンキナーゼALKのリガンド様活性が胎児脊髄に存在する。 2.ErbB-2とTob蛋白質のin vitro相互作用にTobのSer164が必要である。また、Tobが細胞内でりん酸化されていることが示唆された。Tobファミリー蛋白質ANA(=Tob5)とTob4もまた細胞増殖抑制活性を持つ。 3.ショウジョウバエfak cDNAを得た。dFak蛋白質もインテグリンを介するシグナル伝達に関わる。 4.Srcファミリー蛋白質LynはB細胞抗原受容体を介する正のシグナルに関わるのみならず、増殖の負のフィードバック制御にも関わる。B細胞抗原受容体シグナル伝達に関与するFynの機能の多くはLynによって代替されるが、FynはLynの機能の一部しか代替できない。 5.NMDA受容体がSrcファミリーキナーゼFynによってリン酸化され、そのリン酸化反応は癌抑制遺伝子産物の類似体であるPSD95によって促進される。またFynはそのSH2ドメインを介してPSD95のPDZドメインと会合する。 6.7回膜貫通型受容体を介するホルモン等のシグナル伝達に於いて、受容体に会合するGqタイプの3量体G蛋白質によるPLCβの活性化に、Gq蛋白質αサブユニットTyr396残基のチロシンりん酸化が必須である。 7.チロシンフォスファターゼTypが精細胞と卵母細胞に於いて、減数分裂期に特異的に発現する。

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] Hisashi Umemori: "Activation of the G protein Gq/11 through tyrosine phosphorylation of the α subunit." Science. 276. 1878-1881 (1997)
[文献書誌] Toshinori Iwahara: "Molecular characterization of ALK,a receptor tyrosine kinase expressed specifically in the nervous system." Oncogene. 14. 439-449 (1997)
[文献書誌] Hirofumi Nishizumi: "Impaired Ca^<2+> mobilization but not degranulation in Lyn deficient bone marrow-derived mast cells." J.Immunol.158. 2350-2355 (1997)
[文献書誌] Dusco Ilic: "Focal adhesion kinase at the crossroads of signal transduction." J.Cell Sci.110. 401-407 (1997)
[文献書誌] Y.Masuda: "Chromosomal mapping of the mouse and rat brt genes." Genomics.40. 181-184 (1997)
[文献書誌] 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.8. 45-66 (1997)
[文献書誌] Yuji Yamanashi: "Role of tyrosine phosphorylation of HS1 in B cell antigen receptor-mediated apoptosis." Proc.Natl.Acad.Sci.USA. 93. 4181-4186 (1997)
[文献書誌] Akiko Fujimoto-Nishiyama: "A novel zinc finger protein Finb is a trascriptional activator and localized in nuclear bodies." Gene. 195. 267-275 (1997)
[文献書誌] Dusco Ilic: "Skin abnormality in aged fyn^<-1-> fak^<+/-> mice." Carcinogenesis. 18. 1473-1476 (1997)
[文献書誌] Chihiro Hisatsune: "Phosphorylation-dependent regulation of NMDA receptors by calmodulin" J.Biol.Chem.272. 20805-20810 (1997)
[文献書誌] Yutaka Yoshida: "Cloning and characterization of the mouse tob gene" GENE.191. 109-113 (1997)
[文献書誌] Masami Otsuka: "Synthetic inhibitors of regulatory proteins in volved in the signaling pathway of the replication of human immunodeficiency virus 1" Bioorg.Med.Chem.5. 205-215 (1997)
[文献書誌] Tokutaro Yasue: "IgG1 production induced by CD38 ligation and IL-5 require activation of Fyn and Lyn kinases." Proc.Natl.Acad.Sci.USA. 94. 10307-10312 (1997)
[文献書誌] Miho Ohsugi: "Molecular cloning and characterization of a novel,cytoplasmic protein-tyrosine phosphatase that is specifically expressed in spermatocytes." J.Biol.Chem.272. 33092-33099 (1997)
[文献書誌] Masaki Kashiwada: "Tumor necrosis factor receptor-associated factor 6(TRAF6)stimulates extracellular signal-negulated kinase(ERK)activity in CD40 signaling along a Ras-independent pathway" J.Exp.Med.(in press).
[文献書誌] M.Baba: "Mouse germinal center B cells with the xid mutation retain responsiveness to anti-mouse CD40 antibodies but diminish IL-5 responsiveness" Int.Immunol.(in press).
[文献書誌] S.Mizushima: "Cloning and characterization of a cDNA encoding the human homolog of tumor necrosis factor receptor-associated factor-5(TRAF5)" Gene. (in press).
[文献書誌] Kimie Suzuki: "Identification and expression of the Xenopus homolog of mammalian p100-NFκB2." Gene. (in press).
[文献書誌] Kohji Kasahara: "Association of Src family tyrosine kinase Lyn with ganglioside GD_3 in rat brain." J.Biol.Chem.(in press).
[文献書誌] Yutaka Yoshida: "ANA,a novel member of Tob/BTG1 family,is expressed in the ventricular zone of the devel-oping central nervous system." Oncogene. (in press).
[文献書誌] Hirofumi Nishizumi: "A couble-edged kinase Lyn : a positive and negative regulator for antigen receptor-mediated signals" J.Exp.Med.(in press).

1997 年度 実績報告書

癌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] Hisashi Umemori: "Activation of the G protein Gq/11 through tyrosine phosphorylation of the α subunit." Science. 276. 1878-1881 (1997)

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

[文献書誌] Hirofumi Nishizumi: "Impaired Ca^<2+> mobilization but not degranulation in Lyn deficient bone marrow-derived mast cells." J.Immunol.158. 2350-2355 (1997)

[文献書誌] Dusco Ilic: "Focal adhesion kinase at the crossroads of signal transduction." J.Cell Sci.110. 401-407 (1997)

[文献書誌] Y.Masuda: "Chromosomal mapping of the mouse and rat brt genes." Genomics.40. 181-184 (1997)

[文献書誌] 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.8. 45-66 (1997)

[文献書誌] Yuji Yamanashi: "Role of tyrosine phosphorylation of HS1 in B cell antigen receptor-mediated apoptosis." Proc.Natl.Acad.Sci.USA. 93. 4181-4186 (1997)

[文献書誌] Akiko Fujimoto-Nishiyama: "A novel zinc finger protein Finb is a trascriptional activator and localized in nuclear bodies." Gene. 195. 267-275 (1997)

[文献書誌] Dusco Ilic: "Skin abnormality in aged fyn^<-1-> fak^<+/-> mice." Carcinogenesis. 18. 1473-1476 (1997)

[文献書誌] Chihiro Hisatsune: "Phosphorylation-dependent regulation of NMDA receptors by calmodulin" J.Biol.Chem.272. 20805-20810 (1997)

[文献書誌] Yutaka Yoshida: "Cloning and characterization of the mouse tob gene" GENE.191. 109-113 (1997)

[文献書誌] Masami Otsuka: "Synthetic inhibitors of regulatory proteins in volved in the signaling pathway of the replication of human immunodeficiency virus 1" Bioorg.Med.Chem.5. 205-215 (1997)

[文献書誌] Tokutaro Yasue: "IgG1 production induced by CD38 ligation and IL-5 require activation of Fyn and Lyn kinases." Proc.Natl.Acad.Sci.USA. 94. 10307-10312 (1997)

[文献書誌] Miho Ohsugi: "Molecular cloning and characterization of a novel,cytoplasmic protein-tyrosine phosphatase that is specifically expressed in spermatocytes." J.Biol.Chem.272. 33092-33099 (1997)

[文献書誌] Masaki Kashiwada: "Tumor necrosis factor receptor-associated factor 6(TRAF6)stimulates extracellular signal-negulated kinase(ERK)activity in CD40 signaling along a Ras-independent pathway" J.Exp.Med.(in press).

[文献書誌] M.Baba: "Mouse germinal center B cells with the xid mutation retain responsiveness to anti-mouse CD40 antibodies but diminish IL-5 responsiveness" Int.Immunol.(in press).

[文献書誌] S.Mizushima: "Cloning and characterization of a cDNA encoding the human homolog of tumor necrosis factor receptor-associated factor-5(TRAF5)" Gene. (in press).

[文献書誌] Kimie Suzuki: "Identification and expression of the Xenopus homolog of mammalian p100-NFκB2." Gene. (in press).

[文献書誌] Kohji Kasahara: "Association of Src family tyrosine kinase Lyn with ganglioside GD_3 in rat brain." J.Biol.Chem.(in press).

[文献書誌] Yutaka Yoshida: "ANA,a novel member of Tob/BTG1 family,is expressed in the ventricular zone of the devel-oping central nervous system." Oncogene. (in press).

[文献書誌] Hirofumi Nishizumi: "A couble-edged kinase Lyn : a positive and negative regulator for antigen receptor-mediated signals" J.Exp.Med.(in press).

1997 年度実績報告書

山本雅東京大学, 医科学研究所, 教授 (40134621)