| Project/Area Number |
12558080
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Functional biochemistry
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
KIKUCHI Akira Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (10204827)
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| Co-Investigator(Kenkyū-buntansha) |
KISHIDA Michiko Hiroshima University, Faculty of Medicine, Teaching Associate, 医学部, 教務員 (40274089)
KISHIDA Shosei Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 講師 (50274064)
ASAHARA Toshimasa Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (70175850)
AKAHANE Koichi Dai-Ichi Pharmaceutics, Chief Researcher, 創薬第四研究所, 主任研究員
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2001: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥9,700,000 (Direct Cost: ¥9,700,000)
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| Keywords | Wnt signaling / Axin / β-catenin / Axam / Duplin / Idax / genetic diagnosis / SUMO化 / 核移行 / APC / β-catenin / GSK-3β / リン酸化 |
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| Research Abstract |
We have identified three novel proteins that regulate the Wnt signaling pathway in this project. They are Axin-binding, Dvl-binding, and β-catenin-binding proteins, and we designated them Axam, Idax, and Duplin, respectively. Axam has nuclear localization signal (NLS) at the N-terminus and Axin-binding domain in its central region. Furthermore, Axam shares high homology with the catalytic domain of Senp1, which is a SUMO specific protease. Indeed, Axam showed an desumoylation activity. Axam stimulated degradation of β-catenin in mammalian cells and inhibited axis formation in Xenopus embryos. Catalyticaly inactive mutant of Axam reduced these activity. Therefore, sumoylation may be involved in the Wnt signaling pathway. Idax does not share any homology with other proteins. Idax suppressed Wnt dependent β-catenin accumulation and axis formation by inhibiting the binding of Dvl to Axin. Duplin has NLS and β-catenin-binding domain in its C-treminus. Although Duplin inhibited β-catenin-dependent Tcf activation and axis formation, the Duplin mutant that lacks NLS lost these activities, suggesting that Duplin must be in the nucleus to exert its functions. Taken together, Axam, Idax, and Duplin act as a negative regulator of the Wnt signaling pathway. Screening of mutations of these novel molecules in human cancers remains to be clarified.
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