| Project/Area Number |
12219201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | The University of Tokyo |
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Principal Investigator |
YAMAMOTO Tadashi The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (40134621)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Toru The University of Tokyo, Institute of Medical Science, Associate Professor, 医科学研究所, 助手 (50334280)
吉田 富 東京大学, 医科学研究所, 日本学術振興会特別研究員
藤元 次郎 東京大学, 医科学研究所, 助手 (60282521)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥233,700,000 (Direct Cost: ¥233,700,000)
Fiscal Year 2004: ¥48,000,000 (Direct Cost: ¥48,000,000)
Fiscal Year 2003: ¥49,500,000 (Direct Cost: ¥49,500,000)
Fiscal Year 2002: ¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 2001: ¥54,000,000 (Direct Cost: ¥54,000,000)
Fiscal Year 2000: ¥37,200,000 (Direct Cost: ¥37,200,000)
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| Keywords | cancer / cell growth / signal transduction- / tumor suppressor gene / protein phosphorylation / transcription factor complex / gene manipulated mice / RNAi / 蛋白質 / 転写複合体 / プロテオーム / 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 / 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 / G2-Mチェックポイント / G1期制御 |
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| Research Abstract |
We showed the followings through the studies on cell growth regulation with special interest in protein phosphorylation. 1. Tob (1) Tob functions as a tumor suppressor because #1: tob suppresses cell growth when overexpressed, #2: tob-deficient mice are prone to cancer, and #3: expression of tob mRNA is often suppressed in various human tumors. (2) Tob becomes phosphorylated by Erk1/2 upon growth factor stimulation, which results in the loss of anti-proliferative activity of Tob. (3) Tob participates in transcription regulation because #1: Tob associate with HDAC and suppresses transcription of the cyclin Dl gene, #2: Tob regulates BMP signaling through its interaction with Smads. Consequently, tob-deficient mice develop an osteopetrotic phenotype. #3: Tob complexes with the NOT transcription machinery that consists of at least 10 Cnot proteins (Cnot1-10). Among Cnot proteins Cnot7 interacts with RXRβ, and like RXRβ-deficient mice Cnot7-deficient mice are sterile because of Oligo-asthe
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no-teratozoospermia. (4) Tob shuttles between nucleus and cytoplasm. In the cytoplasm Tob associates with polyA binding protein and regulates translation of mRNA. 2. Tyosine phosphorylation (1) Cbl-c induces v-Src ubiquitination and degradation, and thereby suppresses v-Src-mediated malignant transformation. (2) Agonistic monoclonal antibody we produced activates receptor tyrosine kinase ALK on the surface of PC12 cells, and induces their proliferation and neuronal differentiation. (3) ALK utilizes SNT2 adaptor protein for cell signaling, which is relevant to malignant cell transformation by activated ALK. 3. M phase kinases (1) Overexpression of human homologs of drosophila tumor suppressor proteins LATS1/2 results in M phase arrest. (2) RNAi-mediated down-regulation of LATS2-interacting protein Ajuba induces inhibition of spindle formation and chromosome segregation. (3) Ajuba also negatively regulates Wnt signaling through its interaction with β-catenin. (4) Phosphorylation of chromokinesin Kid by Cdc2 is important for chromosome dynamics and M phase progression. These data contributes to deepening our understanding on cell growth regulation. Less
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