2002 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増殖と細胞癌化の制御

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 / 細胞周期 / シグナル伝達 / 蛋白質リン酸化反応 / LATSファミリー / G1制御 / Tobファミリー蛋白質 / アダプター分子
Research Abstract	休止期の細胞が細胞周期に進み、細胞周期が進行する過程は蛋白質リン酸化により、巧みに制御されている。言うまでもなく細胞周期の逸脱は癌発症を促すものである。本研究では、哺乳類細胞の増殖・分化の基盤となっている増殖シグナル伝達機構や細胞周期の調節に焦点をあて、細胞膜からのチロシンキナーゼ活性を基点とする細胞の増殖・分化シグナルが細胞周期制御のシグナルに変換されていく分子機構の解明を試みる。また、M期進行の制御機構を蛋白質リン酸化反応に着目して解析することも目的としている。今年度は細胞周期制御蛋白質TobとLATS2について以下を明らかにした。(1)細胞増殖抑制蛋白質Tobについて以下の結果を得た(a)Tobは核移行シグナルと核排出シグナルを有する。核ではHDACと会合して<I>cyclin D1</I>発現のco-repressorとして作用し、またHAT活性を持つp300/CBPと会合してp21<SUP>waf</SUP>発現のp53非依存的co-activatorとして作用する。更にTobは細胞質ではiPABP(誘導性poly A結合蛋白質)と会合し、IL2 mRNA等の翻訳の負の制御に関与する。(b)Tob mRNA低発現肺癌細胞株を5-aza-2'-deoxycytidine処理するとTobの発現が上昇するので、epigeneticなTobの発現変化が癌化に関わる可能性がある。(c)Tobは非リン酸化状態でCaf1 (ccr4-not associated factor 1)と会合し、Erk1/2でリン酸化されるとその会合能が低下する。X線結晶解析上Caf1-Tob複合体はエクソヌクレアーゼIと類似の構造をもち、またCaf1-Tob複合体はヌクレアーゼ活性を持つ。これは、Tobの作用機構を探る新たな視点となる。(c)Caf1欠損マウスは精子形成が不全である。この表現形はRXRβ欠損マウスと類似し、またTobとCaf1はRXRβと機能的に相互作用する。興味深いことにTob, Tob2二重欠損変異マウスの精子数は減少している。(2)M期チェックポイント蛋白質LATS2やLATS2会合蛋白質AjubaをRNAiで欠損させたHeLa細胞では、紡錘体の形成阻害と異常染色体分配が観察される。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Kohno M: "CD151 Enhances cell motility and metastasis of cancer cells in the presence of focal adhesion kinase"Int. J. Cancer. 97. 336-343 (2002)
[Publications] Yokoyama K: "BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP3 receptor"EMBO J.. 21. 1-10 (2002)
[Publications] Hashimoto R: "Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons : Involvement of NMDA receptor inhibition by decreasing NR2B tyrosine phosphorylation"J. Neurochem. 80. 589-597 (2002)
[Publications] Kitagawa D: "Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation"J. Biol. Chem.. 277. 366-371 (2002)
[Publications] Usui M: "Enhancing dfect of Tob deficiency on bone formation is spesific to BMP-induced osteogenesis"J. Bone Miner. Res.. 17. 1026-1033 (2002)
[Publications] Kono H: "Spatial raft coalescence represents an initial step in Fc gamma R signaling"J. Immunol. 169. 193-203 (2002)
[Publications] Gurd JW: "Differential effects of hypoxia-ischemia on subunit expression and tyrosine phosphorylation of the NMDA receptor in 7-and 21-day-old rats"J. Neurochem.. 82. 848-856 (2002)
[Publications] Naito A: "TRAF6-deficient mice display hypohidrotic ectodermal dysplasia"Proc Natl Acad Sci USA. 99. 8766-8771 (2002)
[Publications] Yasuda T: "Cbl-b positively regulates Btk-mediated activation of phospholipase C-γ2 in B cells"J. Exp. Med.. 196. 51-63 (2002)
[Publications] Suzuki T: "Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation"Genes & Dev. 16. 1357-1370 (2002)
[Publications] Suetsugu S: "Sustained activation of N-WASP through phosphorylation is essential for neurite extension"Dev Cell. 5. 645-658 (2002)
[Publications] Yajima J: "The human chromokinesin Kid is a plus-end directed microtubule-based motor"EMBO J.. (in press).
[Publications] Alvestad RM: "Tyrosine dephosphorylation and ethanol inhibition of NMDA receptor function"J Biol Chem. (in press).
[Publications] Umemori H: "Impairment of N-methyl-D-aspartate receptor-controlled motor activity in Lyn-deficient mice"Neurosci. (in press).
[Publications] Kuo ML: "Arf induces p53-dependent and independent anti-proliferative genes"Cancer Res.. (in press).
[Publications] Yoshida Y: "Tob proteins enhance inhibitory-smad-receptor interaction to repress BMP signaling"Mech Dev.. (in press).
[Publications] Ohsugi M: "Cdc2-mediated phosphorylation of chromokinesin Kid controls its distribution to spindle and chromosomes"EMBO J. (in press).
[Publications] Nakazawa T: "p25OGAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the NMDA receptor signaling"Mol Biol Cell. (in press).

2002 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増殖と細胞癌化の制御

Principal Investigator

山本 雅 東京大学, 医科学研究所, 教授 (40134621)

Research Products

[Publications] Kohno M: "CD151 Enhances cell motility and metastasis of cancer cells in the presence of focal adhesion kinase"Int. J. Cancer. 97. 336-343 (2002)

[Publications] Yokoyama K: "BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP3 receptor"EMBO J.. 21. 1-10 (2002)

[Publications] Hashimoto R: "Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons : Involvement of NMDA receptor inhibition by decreasing NR2B tyrosine phosphorylation"J. Neurochem. 80. 589-597 (2002)

[Publications] Kitagawa D: "Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation"J. Biol. Chem.. 277. 366-371 (2002)

[Publications] Usui M: "Enhancing dfect of Tob deficiency on bone formation is spesific to BMP-induced osteogenesis"J. Bone Miner. Res.. 17. 1026-1033 (2002)

[Publications] Kono H: "Spatial raft coalescence represents an initial step in Fc gamma R signaling"J. Immunol. 169. 193-203 (2002)

[Publications] Gurd JW: "Differential effects of hypoxia-ischemia on subunit expression and tyrosine phosphorylation of the NMDA receptor in 7-and 21-day-old rats"J. Neurochem.. 82. 848-856 (2002)

[Publications] Naito A: "TRAF6-deficient mice display hypohidrotic ectodermal dysplasia"Proc Natl Acad Sci USA. 99. 8766-8771 (2002)

[Publications] Yasuda T: "Cbl-b positively regulates Btk-mediated activation of phospholipase C-γ2 in B cells"J. Exp. Med.. 196. 51-63 (2002)

[Publications] Suzuki T: "Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation"Genes & Dev. 16. 1357-1370 (2002)

[Publications] Suetsugu S: "Sustained activation of N-WASP through phosphorylation is essential for neurite extension"Dev Cell. 5. 645-658 (2002)

[Publications] Yajima J: "The human chromokinesin Kid is a plus-end directed microtubule-based motor"EMBO J.. (in press).

[Publications] Alvestad RM: "Tyrosine dephosphorylation and ethanol inhibition of NMDA receptor function"J Biol Chem. (in press).

[Publications] Umemori H: "Impairment of N-methyl-D-aspartate receptor-controlled motor activity in Lyn-deficient mice"Neurosci. (in press).

[Publications] Kuo ML: "Arf induces p53-dependent and independent anti-proliferative genes"Cancer Res.. (in press).

[Publications] Yoshida Y: "Tob proteins enhance inhibitory-smad-receptor interaction to repress BMP signaling"Mech Dev.. (in press).

[Publications] Ohsugi M: "Cdc2-mediated phosphorylation of chromokinesin Kid controls its distribution to spindle and chromosomes"EMBO J. (in press).

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

山本雅東京大学, 医科学研究所, 教授 (40134621)