2021 Fiscal Year Annual Research Report
ストレスメディエーターClaspinによるストレス反応の統合的な制御機構の解明
| Project/Area Number |
19K16367
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| Research Institution | Tokyo Metropolitan Institute of Medical Science |
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Principal Investigator |
楊 其駿 公益財団法人東京都医学総合研究所, 基礎医科学, 研究員 (80792647)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | Claspin / serum stimulation / PI3 kinase / PDK1 / mTOR |
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| Outline of Annual Research Achievements |
Claspin plays multiple important roles in regulation of DNA replication as a mediator for the cellular response to replication stress, an integral replication fork factor that facilitates replication fork progression and a factor that promotes initiation by recruiting Cdc7 kinase. Here, we report a novel role of Claspin in growth recovery from serum starvation, which requires the activation of PI3 kinase (PI3K)- PDK1-Akt-mTOR pathways. In the absence of Claspin, cells do not proceed into S phase and eventually die partially in a ROS- and p53-dependent manner. Claspin directly interacts with PI3K and mTOR, and is required for activation of PI3K-PDK1-mTOR and for that of mTOR downstream factors, p70S6K and 4E-BP1, but not for p38 MAPK cascade during the recovery from serum starvation. PDK1 physically interacts with Claspin, notably with CKBD, in a manner dependent on phosphorylation of the latter protein, and is required for interaction of mTOR with Claspin. Thus, Claspin plays a novel role as a key regulator for nutrition-induced proliferation/survival signaling by activating the mTOR pathway. The results also suggest a possibility that Claspin may serve as a common mediator that receives signals from different PI3K-related kinases and transmit them to specific downstream kinases.
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