| Project/Area Number |
18K07238
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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 50010:Tumor biology-related
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| Research Institution | University of Miyazaki |
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Principal Investigator |
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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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | PRMT5 / HSP90 / NDRG2 / ATL / がん / synthetic lethality / アルギニンメチル化 / 癌 |
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| Outline of Final Research Achievements |
We found that the tumor suppressor gene NDRG2 induces the dephosphorylation of various signaling factors through the recruitment of PP2A, resulting in negatively the suppression of the signal transduction pathways. Our previous studies demonstrated that the expression of NDRG2 was significantly down-regulated in many type of tumors, leading to the progression of tumor development through the aberrant activation of the signal transduction pathways. We identified a novel NDRG2/PP2A-binding protein PRMT5 by Comprehensive analysis. The highly phosphorylated PRMT5 in NDRG2 deficient tumor was localized mainly in the cytoplasm, and modulated arginine methylation of cytoplasmic proteins. Therefore, the purpose of this study is to comprehensively analyze the abnormal arginine methylation caused by PRMT5 activity through the decrease of NDRG2 expression, and to elucidate the mechanism of tumorigenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
NDRG2/PP2Aの脱リン酸化基質候補としてアルギニンメチル基酵素群であるPRMT5を新規に同定した。正常細胞ではPRMT5は核に偏在し、ヒストン等をアルギニンメチル化し遺伝子発現制御を行なっている。一方で、NDRG2欠損がんでは細胞質に主に局在し、異なった基質をアルギニンメチル化し腫瘍発症進展に関与している。これらの見地を基盤としたPRMT5機構解析は、NDRG2欠損がん・白血病に選択的に効果のある阻害剤開発に繋がる。さらに、NDRG2は全がんの約42-85%で高頻度に遺伝子発現低下が認められ、適応範囲は非常に広く社会的にも医療的にも貢献ができると考えている。
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