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SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress
Takanori Nakamura1, Haruo Saito, Mutsuhiro Takekawa
1Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Nature Communications
|May 9, 2013
Summary
Polo-like kinase 4 (PLK4) activation by SAPKKKs promotes centrosome duplication. Stress-induced signals and p53 normally prevent supernumerary centrosomes, but MKK4/p53 inactivation in cancer cells leads to centrosome amplification.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Polo-like kinase 4 (PLK4) is crucial for centrosome duplication.
- PLK4 hyperactivation leads to supernumerary centrosomes, a hallmark of cancer.
Purpose of the Study:
- To elucidate the regulatory mechanisms of PLK4 during stress response.
- To investigate the role of SAPKKKs and p53 in controlling centrosome duplication under stress.
- To understand how MKK4 and p53 inactivation contributes to centrosome amplification in cancer cells.
Main Methods:
- Investigated the direct phosphorylation and activation of PLK4 by SAPKKKs.
- Analyzed the opposing roles of stress-induced PLK4 activation and SAPK activation on centrosome duplication.
- Examined the role of p53 in downregulating PLK4 expression during late-phase stress response.
- Assessed the impact of simultaneous p53 and MKK4 inactivation on centrosome integrity under genotoxic stress.
Main Results:
- Stress-activated protein kinase kinase kinases (SAPKKKs) directly phosphorylate and activate PLK4.
- Stress response involves a balance between PLK4 activation (promoting duplication) and SAPK activation (inhibiting duplication).
- p53 downregulates PLK4 expression in late-stage stress, preventing centrosome amplification.
- Simultaneous inactivation of p53 and MKK4 leads to persistent PLK4 activity and centrosome amplification under stress, particularly in cancer cells.
Conclusions:
- A novel mechanism involving SAPKKKs, SAPKs, and p53 regulates centrosome duplication during stress.
- MKK4 possesses an uncharacterized tumor-suppressive function by preventing centrosome amplification.
- Inactivation of MKK4 and p53 in cancer cells creates a vulnerability for developing supernumerary centrosomes under genotoxic stress.
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