Elucidation of a novel homeostatic mechanism by enhanced O-GlcNAcylation under proteasome dysfunction
| Project/Area Number |
19K07062
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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 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Hamazaki Jun 東京大学, 大学院薬学系研究科(薬学部), 助教 (80533588)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | プロテアソーム / ユビキチン / O-GlcNAc / タンパク質分解 |
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| Outline of Research at the Start |
近年になりタンパク質分解酵素複合体プロテアソームの阻害剤が難治性多発性骨髄腫の治療薬として使用されているが、薬剤耐性株に対する有効な対応策・治療戦略が確立していない。最近、申請者らはプロテアソーム不全時の恒常性維持にO-GlcNAc修飾タンパク質亢進が重要であることを見出した。本研究ではO-GlcNAc修飾タンパク質亢進による恒常性維持機構の分子メカニズム解明を軸にプロテアソーム不全に起因する病態発症機構の理解や、がん治療におけるプロテアソーム阻害剤耐性細胞に対する新たな分子標的薬ターゲット・治療アプローチの創出を目指す。
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| Outline of Final Research Achievements |
The 26S proteasome is a protein complex that plays a role in protein degradation and plays an essential role in all eukaryotic cells. We identified that the enhanced O-GlcNAcylation of proteins is important to cellular proteostasis under proteasome dysfunction. In this study, we investigated the role and physiological importance of novel factors identified by mass spectrometry or genetic explorations to elucidate the molecular mechanism of O-GlcNAcylation. We identified the novel factor that act on the regulation of proteasome function and clarify their function of them, but there is a need for detailed verification and further development of research.
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| Academic Significance and Societal Importance of the Research Achievements |
哺乳類プロテアソームの機能制御や生理機能についてはまだ未解明の部分が多く、プロテアソーム機能不全が関与すると考える広範な病態発症の基本原理の理解には課題が多いのが現状である。本研究においてプロテアソーム不全時にどのような細胞応答が生じるかを明らかにし、それを担う新たなプロテアソーム制御因子の同定と機能解明を進めたことは学術的にも重要性は高く、治療アプローチの作用点として今後研究が発展することで応用研究の基盤としても将来性が高い。
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency2021
Author(s)
Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
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Journal Title
Nature Communications
Volume: 12
Issue: 1
Pages: 0-0
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] NRF3-POMP-20S proteasome assembly axis promotes cancer development via ubiquitin-independent proteolysis of p53 and Rb.2020
Author(s)
Waku T, Nakamura N, Koji M, Watanabe H, Katoh H, Tatsumi C, Tamura N, Hatanaka A, Hirose S, Katayama H, Tani M, Kubo Y, Hamazaki J, Hamakubo T, Watanabe A, Murata S, Kobayashi A
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Journal Title
Molecular and Cellular Biology
Volume: -
Issue: 10
Pages: 1-1
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Trans-omics impact of thymoproteasome in cortical thymic epithelial cells.2019
Author(s)
Ohigashi I, Tanaka Y, Kondo K, Fujimori S, Kondo H, Palin A, Hoffmann V, Kozai M, Matsushita Y, Uda S, Motosugi R, Hamazaki J, Kubota H, Murata S, Tanaka K, Katagiri T, Kosako H, Takahama Y
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Journal Title
Cell Reports
Volume: 29
Issue: 9
Pages: 2901-2916
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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