| Project/Area Number |
18K06208
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 44010:Cell biology-related
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Shibuya Hiroshi 東京医科歯科大学, 難治疾患研究所, 教授 (30261324)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | WNK / Wntシグナル / 神経分化 / β-catenin / GID omplex / GID complex / GSK3β / Sgg / Lhx8 / 神経発生 / ユビキチン化 |
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| Outline of Final Research Achievements |
In order to elucidate the function of WNK in the nervous system, we proceeded with the analysis of the Wnt signaling mechanism by WNK, and it was shown that WNK binds to MAEA, which is an E3 ligase, and WNK inhibits the binding between MAEA and β-catenin. It was clarified that the decomposition by the decomposition complex GID was suppressed. Furthermore, when the effect of the WNK inhibitor on the Wnt signal was investigated, it induced ubiquitination and degradation of β-catenin, suppressed the expression of the Wnt target gene, and the WNK inhibitor was less toxic and degraded β-catenin. It was clarified that it efficiently suppresses the formation of colorectal cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでWNKによるWntシグナル分子β-cateninの分解制御機構は全く知られていなかった。本研究によりβ-cateninの新規結合分子を発見し、WNKがβ-cateninのユビキチン化を阻害することでβ-cateninの分解を抑制し、Wntシグナルを制御することを見出した。またWNK阻害剤の投与によりWntシグナルの抑制を介して大腸がん形成を抑えることができたことから、WNKが新たな抗がん剤の標的分子となると期待された。さらに、Wntシグナルの異常な活性化ががん以外の疾患においても観察される現象であることからも、本研究成果は多様な疾患に対する非常に有用な知見となると考えられた。
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