Maintenance of chromosomal stability by stress-responsive signaling systems and its failure in cancer
| Project/Area Number |
24390079
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2012: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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| Keywords | ストレス応答 / p38 / JNK / p53 / 中心体 / MAPキナーゼ / MKK4 / がん / PLK / シグナル伝達 / SAPK |
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| Outline of Final Research Achievements |
In this study, we identified that PLK4, a key regulator for centrosome duplication, is directly phosphorylated and activated by SAPKKKs. Stress-induced PLK4 activation promotes centrosome duplication, whereas stress-induced SAPK activation prevents it. In the early phase of stress response, the balance of these opposing signals prevents centrosome overduplication. However, in the late phase of stress response, p53 downregulates PLK4 expression, thereby preventing sustained PLK4 activity and centrosome amplification. If both p53 and MKK4 are simultaneously inactivated, persistent PLK4 activity combined with the lack of SAPK-mediated inhibition of centrosome duplication conspire to induce supernumerary centrosomes under stress. Indeed, tumour-derived MKK4 mutants induced centrosome amplification under stress, but only in p53-negative cells. Thus, our results reveal a mechanism that preserves the numeral integrity of centrosomes, and an unexplored tumour-suppressive function of MKK4.
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Report
(4 results)
Research Products
(63 results)
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[Journal Article] Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity2015
Author(s)
Sato, Y., Goto, E., Shibata, Y., Kubota, Y., Yamagata, A., Goto-Ito, S., Kubota, K., Inoue, J., Takekawa, M., Tokunaga, F. and Fukai, S.
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Journal Title
Nat. Struct. Mol. Biol.
Volume: 22
Issue: 3
Pages: 222-229
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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