Journal
ONCOGENE
Volume 28, Issue 48, Pages 4295-4305Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.282
Keywords
p53; FoxM1; transcriptional repression; p21; Rb; G2 arrest
Funding
- National Institutes of Health [CA77742]
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The p53 tumor suppressor protein acts as a transcription factor to modulate cellular responses to a wide variety of stresses. In this study we show that p53 is required for the downregulation of FoxM1, an essential transcription factor that regulates many G2/M-specific genes and is overexpressed in a multitude of solid tumors. After DNA damage, p53 facilitates the repression of FoxM1 mRNA, which is accompanied by a decrease in FoxM1 protein levels. In cells with reduced p53 expression, FoxM1 is upregulated after DNA damage. Nutlin, a small-molecule activator of p53, suppresses FoxM1 levels in two cell lines in which DNA damage facilitates only mild repression. Mechanistically, p53-mediated inhibition of FoxM1 is partially p21 and retinoblastoma (Rb) family dependent, although in some cases p21-independent repression of FoxM1 was also observed. The importance of FoxM1 to cell fate was indicated by the observation that G2/M arrest follows FoxM1 ablation. Finally, our results indicate a potential contribution of p53-mediated repression of FoxM1 for maintenance of a stable G2 arrest. Oncogene (2009) 28, 4295-4305; doi: 10.1038/onc.2009.282; published online 14 September 2009
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