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Pro-proliferative FoxM1 is a target of p53-mediated repression

Oncogene volume 28, pages 4295–4305 (2009)Cite this article

Abstract

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.

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Acknowledgements

Ella Freulich provided expert technical assistance. Members of the Prives laboratory are thanked for their support and encouragement. This work was supported by the National Institutes of Health Grant CA77742.

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  1. Department of Biological Sciences, Columbia University, New York, NY, USA

    A M Barsotti & C Prives

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  1. A M Barsotti
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Correspondence to C Prives.

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Barsotti, A., Prives, C. Pro-proliferative FoxM1 is a target of p53-mediated repression. Oncogene 28, 4295–4305 (2009). https://doi.org/10.1038/onc.2009.282

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