2003 Fiscal Year Annual Research Report

蛋白質リン酸化・脱リン酸化反応を介する細胞周期制御と細胞癌化の制御

Research Project

Project/Area Number	12219201
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)	鈴木亨東京大学, 医科学研究所, 助手 (50334280)
Keywords	癌抑制遺伝子 / 蛋白質リン酸化反応 / 細胞周期 / 肺癌細胞株 / 遺伝子欠損マウス / Tob / Caf1 / CCR4 / NOT / LATS / Ndr
Research Abstract	細胞の増殖・分化の基盤となっている細胞周期の調節に焦点をあて、細胞増殖抑制活性を有するTobファミリー蛋白質と、M期キナーゼであることが指摘されているLATS癌抑制遺伝子産物について、その機能・作用機構を、マウス個体、細胞、分子のレベルで解析し、以下を明らかにした。特にこれら蛋白質と発癌との関わりを探ることを意識した。(1)HeLa細胞株より調製したTob複合体のプロテオーム的解析から、TobがCCR4-NOTをコアとする巨大転写因子複合体に会合することを明らかにした。(2)Tobに会合する分子として、新たなWD40リピート含有ユビキチンリガーゼを見いだしWAT120と命名した。さらにWAT120の発現がTobのユビキチン化と分解を誘導することを示した。(3)CCR4-NOT構成成分であるCaf1を欠損するマウスを作成・解析し、Caf1とRXRβが機能的・物理的に相互作用しながら遺伝子発現制御を行い精細胞の分化等に関わることを示した。またCaf1の発現がヒト肺癌細胞株で高頻度に減少していることを見いだした。これらより、TobがCaf1/RXRβ系を制御し、ヒト癌発症に関わる可能性を推察した。(4)癌抑制遺伝子産物であり、M期で機能していることが指摘されているLATSキナーゼに類似するNdr2キナーゼを新たに同定し、Tobがそのキナーゼ活性制御に関わることを示した。(5)LATS標的LIMドメイン含有蛋白質AjubaとZRP1について分子細胞生物学的に解析し、Ajubaがβ-cateninと相互作用しWnt/Winglessシグナル伝達を負に制御しうることを明らかにした。また、ZRP1がアクチン骨格系の制御に関わることを示した。以上より癌抑制遺伝子産物TobファミリーとLATSファミリーの作用機構の理解を深めた。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Yajima J et al.: "The human chromokinesin Kid is a plus-end directed microtubule -based motor"EMBO J. 22. 1067-1074 (2003)
[Publications] Alvestad RM et al.: "Tyrosine dephosphorylation and ethanol inhibition of NMDA receptor function"J Biol Chem. 278. 11020-11025 (2003)
[Publications] Umemori H et al.: "Impairment of N-methyl-D-aspartate receptor-controlled motor activity in Lyn-deficient mice"Neurosci. 118. 709-713 (2003)
[Publications] Kuo ML et al.: "Arf induces p53-dependent and independent anti-proliferative genes"Cancer Res. 63. 1046-1053 (2003)
[Publications] Yoshida Y et al.: "Tob proteins enhance inhibitory-smad-receptor interaction to repress BMP signaling"Mech Dev. 120. 629-637 (2003)
[Publications] Ohsugi M et al.: "Cdc2-mediated phosphorylation of chromokinesin Kid controls its distribution to spindle and chromosomes"EMBO J. 22. 2091-2103 (2003)
[Publications] Nakazawa T et al.: "p25OGAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the NMDA receptor signaling"Mol Biol Cell. 14. 2921-2934 (2003)
[Publications] Yoshida Y.et al.: "Mice lacking a transcriptional corepressor Tob are predisposed to cancer"Genes Dev. 17. 1201-1206 (2003)
[Publications] Taniguchi S et al.: "p25OGAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn"Biochem Biophys Res Commun. 306. 151-155 (2003)
[Publications] Iwanaga K et al.: "Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer"Cancer Lett. 202. 71-79 (2003)
[Publications] Shiroguchi K et al.: "Links The second microtubule-binding site of monomeric kid enhances the microtubule affinity"J Biol Chem. 278. 22460-22456 (2003)
[Publications] Goto J et al.: "Altered gene expression in the adult brain of fyn-deficient mice"Cell Mol Neurobiol. 24. 149-159 (2004)
[Publications] Usui M et al.: "Tob-deficiency super-enhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis"Proc Natl Acad Sci USA. (In press).
[Publications] Kim M et al.: "Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation"Oncogene. (In press).
[Publications] Motegi A.et al.: "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth asrevealed by an agonist anti-ALK monoclonal antibody"J Cell Sci. (In press).
[Publications] Kawa S et al.: "Involvement of BREK, a novel dual-specificity kinase enriched in brain, in NGF signaling. Genes to Cells"Genes to Cells. (In press).
[Publications] Nakamura T et al.: "Oligo-astheno-teratozoospermia in mice lacking Cnot7, a novel regulator of retinoid X receptor beta"Nature Genetics. (In press).
[Publications] 村松正実, 山本雅編著: "改訂4版新遺伝子工学ハンドブック"羊土社, 葛西文明. 334 (2003)

2003 Fiscal Year Annual Research Report

蛋白質リン酸化・脱リン酸化反応を介する細胞周期制御と細胞癌化の制御

Principal Investigator

山本 雅 東京大学, 医科学研究所, 教授 (40134621)

Research Products

[Publications] Yajima J et al.: "The human chromokinesin Kid is a plus-end directed microtubule -based motor"EMBO J. 22. 1067-1074 (2003)

[Publications] Alvestad RM et al.: "Tyrosine dephosphorylation and ethanol inhibition of NMDA receptor function"J Biol Chem. 278. 11020-11025 (2003)

[Publications] Umemori H et al.: "Impairment of N-methyl-D-aspartate receptor-controlled motor activity in Lyn-deficient mice"Neurosci. 118. 709-713 (2003)

[Publications] Kuo ML et al.: "Arf induces p53-dependent and independent anti-proliferative genes"Cancer Res. 63. 1046-1053 (2003)

[Publications] Yoshida Y et al.: "Tob proteins enhance inhibitory-smad-receptor interaction to repress BMP signaling"Mech Dev. 120. 629-637 (2003)

[Publications] Ohsugi M et al.: "Cdc2-mediated phosphorylation of chromokinesin Kid controls its distribution to spindle and chromosomes"EMBO J. 22. 2091-2103 (2003)

[Publications] Nakazawa T et al.: "p25OGAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the NMDA receptor signaling"Mol Biol Cell. 14. 2921-2934 (2003)

[Publications] Yoshida Y.et al.: "Mice lacking a transcriptional corepressor Tob are predisposed to cancer"Genes Dev. 17. 1201-1206 (2003)

[Publications] Taniguchi S et al.: "p25OGAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn"Biochem Biophys Res Commun. 306. 151-155 (2003)

[Publications] Iwanaga K et al.: "Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer"Cancer Lett. 202. 71-79 (2003)

[Publications] Shiroguchi K et al.: "Links The second microtubule-binding site of monomeric kid enhances the microtubule affinity"J Biol Chem. 278. 22460-22456 (2003)

[Publications] Goto J et al.: "Altered gene expression in the adult brain of fyn-deficient mice"Cell Mol Neurobiol. 24. 149-159 (2004)

[Publications] Usui M et al.: "Tob-deficiency super-enhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis"Proc Natl Acad Sci USA. (In press).

[Publications] Kim M et al.: "Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation"Oncogene. (In press).

[Publications] Motegi A.et al.: "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth asrevealed by an agonist anti-ALK monoclonal antibody"J Cell Sci. (In press).

[Publications] Kawa S et al.: "Involvement of BREK, a novel dual-specificity kinase enriched in brain, in NGF signaling. Genes to Cells"Genes to Cells. (In press).

[Publications] Nakamura T et al.: "Oligo-astheno-teratozoospermia in mice lacking Cnot7, a novel regulator of retinoid X receptor beta"Nature Genetics. (In press).

[Publications] 村松正実, 山本雅 編著: "改訂4版 新遺伝子工学ハンドブック"羊土社, 葛西文明. 334 (2003)

山本雅東京大学, 医科学研究所, 教授 (40134621)

[Publications] 村松正実, 山本雅編著: "改訂4版新遺伝子工学ハンドブック"羊土社, 葛西文明. 334 (2003)