期刊
CELL CYCLE
卷 10, 期 24, 页码 4330-4340出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.24.18682
关键词
mutant p53; polo-like kinase 2; gain of function; DNA damage; feed back loop
类别
资金
- Italian Association for Cancer Research (AIRC)
- Italian Association for Cancer Research (AIRC-MFAG) [9046]
- Lega Italiana Tumori
- Ministero della Salute
- Alleanza contro il Cancro, Fondazione Veronesi and INAIL
- European Community (EC) [Active p53, Mutant p53 consortia]
- Ridgefield Foundation
Aberrant activation of kinases has emerged to be a key event along with tumor progression, maintenance of tumor phenotype and response to anticancer treatments. This study documents the existence of an oncogenic autoregulatory feedback loop that includes the polo-like kinase-2 (Snk/Plk2) and mutant p53 proteins. Plk2 protein binds to and phosphorylates mutant p53, thereby potentiating its oncogenic activities. Phosphorylated mutant p53 binds more efficiently to p300, consequently strengthening its own transcriptional activity. Plk2 gene is regulated at a transcriptional level by both wt- and mutant p53 proteins. This leads to growth suppression or enhanced cell proliferation and chemo-resistance, respectively. In turn, the siRNA-mediated knockdown of either mutant p53 or Plk2 proteins significantly curtails the growth properties of tumor cells and their chemo-resistance to anticancer treatments. Therefore, this paper identifies a novel tumor network including Plk2 and mutant p53 proteins whose triggering in response to DNA damage might disclose important implications for the treatment of human cancers.
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