Chk1 function in normal cell cycle and cell viability
| Project/Area Number |
18K06927
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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 48040:Medical biochemistry-related
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| Research Institution | Mie University |
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Principal Investigator |
GOTO Hidemasa 三重大学, 医学系研究科, 教授 (20393126)
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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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | チェックポイントキナーゼ１（Chk1） / 細胞生存 / 細胞周期 / チェックポイント / チェックポイントキナーゼ１ / Chk1 |
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| Outline of Final Research Achievements |
Chk1 is an evolutionally conserved protein kinase that transduces checkpoint signals from ATR to Cdc25A during DNA damage response (DDR). In mammals, Chk1 also controls cellular proliferation even in the absence of exogenous DNA damage. Here, we have established near-diploid HCT116 cell lines containing endogenous Chk1 protein tagged with a minimum auxin-inducible degron (mAID) using a CRISPR/Cas9-based gene editing. Establishment of these cells enabled us to induce specific and rapid depletion of the endogenous Chk1 protein, which resulted in aberrant accumulation of DNA damage factors that induced cell-cycle arrest at S or G2 phase. Cdc25A stabilized upon Chk1 depletion before the accumulation of DNA damage factors. Simultaneous depletion of Chk1 and Cdc25A partially suppressed the defects caused by Chk1 single depletion. These results indicate that, similar to its function in DDR, Chk1 controls normal cell-cycle progression mainly by inducing Cdc25A degradation.
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| Academic Significance and Societal Importance of the Research Achievements |
Chk1抑制による殺細胞効果は、正常細胞よりがん細胞において顕著であるため、多くの薬剤会社がChk1阻害剤を抗がん治療の分子標的薬として開発を続けている。そのため、Chk1を介した細胞生存シグナルの解明は、なぜ、Chk1阻害剤ががん細胞により効果的なのかを明らかにするうえでも重要であるが、その詳細はほとんど解明されていなかった。当研究により、DNA損傷を受けた細胞と受けていない細胞でChk1の下流のシグナル伝達経路が大きく変化しないことが明らかになった。このことは、Chk1阻害剤を臨床現場で応用していく際に正常細胞への損傷も常に考慮すべきであることを強く示唆しているものといえる。
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Report
(4 results)
Research Products
(9 results)
