2014 Fiscal Year Final Research Report
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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| Keywords | ストレス応答 / p38 / JNK / p53 / 中心体 |
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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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| Free Research Field |
分子細胞生物学
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