| Project/Area Number |
12219214
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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 | HIROSHIMA UNIVERSITY |
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Principal Investigator |
KIKUCHI Akira Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (10204827)
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| Co-Investigator(Kenkyū-buntansha) |
KISHIDA Shosei Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (50274064)
YAMAMOTO Hideki Hiroshima University, Graduate School of Biomedical Sciences, Research Associate, 大学院医歯薬学総合研究科, 助手 (20372691)
HINO Shin-ichiro Hiroshima University, Graduate School of Biomedical Sciences, Research Associate, 大学院医歯薬学総合研究科, 助手 (00372699)
KISHIDA Michiko Hiroshima University, Faculty of Medicine, Teaching Associate, 医学部, 教務員 (40274089)
小山 眞也 広島大学, 大学院・医歯薬学総合研究科, 助教授 (00186834)
安東 知子 広島大学, 医学部, 助手 (20294548)
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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 |
¥199,400,000 (Direct Cost: ¥199,400,000)
Fiscal Year 2004: ¥47,500,000 (Direct Cost: ¥47,500,000)
Fiscal Year 2003: ¥48,400,000 (Direct Cost: ¥48,400,000)
Fiscal Year 2002: ¥39,000,000 (Direct Cost: ¥39,000,000)
Fiscal Year 2001: ¥33,500,000 (Direct Cost: ¥33,500,000)
Fiscal Year 2000: ¥31,000,000 (Direct Cost: ¥31,000,000)
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| Keywords | cancer / metastasis / wnt signal / β-catenin / GSK-3 / Tcf / phosphorylation / sumoylation / Wnt / ユビキチン化 / Tcf-4 / PIASy / PKA / エンドサイトーシス / APC / 蛋白質分解 / 癌 / カゼインキナーゼ / Axam / Wntシグナル伝達経路 / カゼインキナーゼI / 蛋白質リン酸化酵素PP2A / ストレス応答 / Axin / Bul / Rsp5 / Rog1 |
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| Research Abstract |
The following observations concerning Wnt signal and carcinogenesis were obtained in this research.
(1) Regulation of β-catenin stability
APC formed a complex with GSK-3 through Axin and enhanced GSK-3-dependent phosphorylation of β-catenin. The B subunit of PR61 bound to Axin and enhanced β-catenin-dependent Tcf-4 transcriptional activity. PKA phosphorylated β-catenin and inhibited its ubiquitination, thereby stabilizing β-catenin. Therefore, it is clear that phosphorylation events of the molecules in the Axin complex are important for the regulation of β-catenin stability.
(2) Identification of novel regulatory proteins in the Wnt signal pathway
Axam, Idax, and Duplin were identified as novel Axin-, Dvl-, and β-catenin-binding proteins, respectively. All of them negatively regulated the Wnt signal, and their knockout mice were embryonic lethal, indicating that these novel proteins were important for developmental process.
(3) Regulation of the Wnt signal pathway through sumoylation
Axam in
… More
duced degradation of β-catenin through its desumoylation activity. Tcf-4 was modified with SUMO and sumoylation enhanced the transcriptional activity of Tcf-4. Therefore, sumoylation and desumoylation are important for the regulation of the Wnt signal.
(4) Identification of GSK-3-binding proteins and their functions
AKAP220 and h-prune were identified as GSK-3 binding proteins. AKAP220 bound to PKA and was involved in the regulation of GSK-3 activity. H-prune was localized to focal adhesions and involved in cell migration through the binding to GSK-3. Therefore, GSK-3 determines its activity and functions, dependent on the binding partners.
(5) Functions of metastatic related proteins
Imunohistochemical analyses with the antibodies against the proteins described above revealed that h-prune and Wnt-5a are highly expressed in colon cancer, pancreatic cancer, and malignant melanoma. Their expression levels were correlated with the degree of the invasiveness of tumors and lymph node metastasis. These antibody may be useful for diagnosis for tumor aggressiveness. Less
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