2013年4月30日
SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress
Nature Communications
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回数 : 73
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- ,
- 巻
- 4
- 号
- 1
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/ncomms2752
- 出版者・発行元
- Springer Science and Business Media LLC
Polo-like kinase 4 is essential for centrosome duplication, but its hyperactivation causes
supernumerary centrosomes. Here we report that polo-like kinase 4 is directly phosphorylated and activated by stress-activated protein kinase kinase kinases (SAPKKKs). Stress-induced polo-like kinase 4 activation promotes centrosome duplication, whereas stress-induced SAPK activation prevents centrosome duplication. 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 polo-like kinase 4 expression, thereby preventing sustained polo-like kinase 4 activity and centrosome amplification. If both p53 and the SAPKK MKK4 are simultaneously inactivated, as is frequently found in cancer cells, persistent polo-like kinase 4 activity combined with the lack of SAPK-mediated inhibition of centrosome duplication conspire to induce supernumerarycentrosomes under stress. Indeed, tumour-derived MKK4 mutants induced centrosome amplification under genotoxic 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.
supernumerary centrosomes. Here we report that polo-like kinase 4 is directly phosphorylated and activated by stress-activated protein kinase kinase kinases (SAPKKKs). Stress-induced polo-like kinase 4 activation promotes centrosome duplication, whereas stress-induced SAPK activation prevents centrosome duplication. 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 polo-like kinase 4 expression, thereby preventing sustained polo-like kinase 4 activity and centrosome amplification. If both p53 and the SAPKK MKK4 are simultaneously inactivated, as is frequently found in cancer cells, persistent polo-like kinase 4 activity combined with the lack of SAPK-mediated inhibition of centrosome duplication conspire to induce supernumerarycentrosomes under stress. Indeed, tumour-derived MKK4 mutants induced centrosome amplification under genotoxic 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.
- リンク情報
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- DOI
- https://doi.org/10.1038/ncomms2752 本文へのリンクあり
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000318872100132&DestApp=WOS_CPL
- 共同研究・競争的資金等の研究課題
- SAPK新規標的分子の中心体複製抑制機構及びPLK4の中心体移行機構の解明
- URL
- https://www.nature.com/articles/ncomms2752.pdf 本文へのリンクあり
- URL
- https://www.nature.com/articles/ncomms2752 本文へのリンクあり
- ID情報
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- DOI : 10.1038/ncomms2752
- ISSN : 2041-1723
- eISSN : 2041-1723
- Web of Science ID : WOS:000318872100132