| Project/Area Number |
18K07311
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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 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
Shibata Norihito 国立医薬品食品衛生研究所, 生化学部, 室長 (30391973)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 脱ユビキチン化酵素 / がん特異的融合タンパク質 / タンパク質分解 / がん / 融合キナーゼタンパク質 |
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| Outline of Final Research Achievements |
Recently, fusion genes resulting from chromosomal rearrangements are found in a variety of tumor cells. Some of the products of such fusion genes are known to be driver oncogenic fusion proteins. In this study, we found that at least some of these oncogenic fusion proteins can be stably expressed in tumor cells by deubiquitylation. We also found that the deubiquitylating enzyme USP25 is involved in the stable expression of BCR-ABL, an oncogenic fusion kinase protein. In addition, it has been shown that deletion of USP25 expression or pharmacological inhibition of its activity leads to a decrease in BCR-ABL protein expression and suppression of the proliferation of BCR-ABL-positive cells. These results indicate that deubiquitylating enzyme would be a promising therapeutic target for the tumor caused by the oncogenic fusion proteins.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、脱ユビキチン化酵素ががん特異的融合タンパク質を安定化している可能性を提起した。これはがん細胞ではその増殖に必要なタンパク質を安定発現させる機構が存在していることを明らかにした点で学術的な意義が大きい。また脱ユビキチン化酵素ががん特異的融合タンパク質の創薬標的になり得ることを示したことから、標的タンパク質自体の酵素活性阻害ではなく分解を誘導する医薬品開発の可能性を提示することになり、他の様々な標的タンパク質に対する分子標的治療薬の開発にも適用できる波及効果の高い創薬コンセプトであると言える。
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