Identification of non-canonical degradation pathway of HIF-1 alpha promoted by de-ubiqutinating enzyme inhibitor.
| Project/Area Number |
16K07114
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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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| Research Field |
Tumor biology
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| Research Institution | Kyoto University |
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Principal Investigator |
Hattori Akira 京都大学, 薬学研究科, 准教授 (50300893)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | ユビキチン / 脱ユビキチン化酵素活性 / 低酸素誘導因子 / プロテアソーム / タンパク質分解 / 低酸素応答 / HIF-1 / 脱ユビキチン化酵素 / p38MAPキナーゼ / anisomycin |
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| Outline of Final Research Achievements |
We found that inhibition of de-ubiquitinating enzymes (DUB), which release ubiquitin (Ub) moieties from Ub chain, promoted a degradation of hypoxia-inducible factor(HIF)-1α through a unidentified proteasome-independent pathway. We revealed that WP1130, a DUB inhibitor, activated the p38 MAP kinase pathway and anisomycin, a p38 MAP kinase activator, promoted the degradation of HIF-1α which accumulated by the proteasome inhibition. These results suggested that WP1130 activates non-canonical HIF-1α degradation pathway via p38 MAP kinase pathway. We constructed a series of C-terminal deletion mutants and demonstrated that a region between residues 375 and 600 of HIF-1α is essential for the induction of non-canonical degradation pathway. Study employing various protease inhibitors including ALLN, a calpain-I inhibitor, suggested that calpain-I inhibitor ALLN-sensitive protease is involved in the WP1130-induced degradation of HIF-1α accumulated by proteasome-inhibition,
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| Academic Significance and Societal Importance of the Research Achievements |
がん治療におけるHIF-1機能制御の有効性は既に広く認識されている。本研究の結果、脱ユビキチン化酵素の阻害によって誘導される新しいHIF-1α分解経路が、がん悪性化に対する新しい制御点として機能しうることが明らかとなった。
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Report
(4 results)
Research Products
(8 results)
