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

Oncogene. 2009 Dec 3;28(48):4295-305. doi: 10.1038/onc.2009.282. Epub 2009 Sep 14.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Cycle Proteins / physiology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage
  • Down-Regulation / drug effects*
  • Down-Regulation / physiology
  • E2F1 Transcription Factor / physiology
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / pharmacology*
  • Humans
  • Ki-67 Antigen / physiology
  • NF-kappa B / physiology
  • Neoplasms / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factors / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*


  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F1 Transcription Factor
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Ki-67 Antigen
  • NF-kappa B
  • Transcription Factors
  • Tumor Suppressor Protein p53