Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53

Oncogene. 2003 Aug 28;22(36):5586-91. doi: 10.1038/sj.onc.1206845.

Abstract

Dual-specificity phosphatase 5 (DUSP5), a VH1-like enzyme that hydrolyses nuclear substrates phosphorylated on both tyrosine and serine/threonine residues, has a potential role in deactivation of mitogen- or stress-activated protein kinases. Using cDNA-microarray technology, we found that the expression of DUSP5 mRNA was dramatically increased by exogenous p53 in U373MG, a p53-mutant glioblastoma cell line. Transcription of DUSP5 was also remarkably activated by endogenous p53 in response to DNA damage in colon-cancer cells (p53+/+) that contained wild-type p53, but not in p53-/- cells. Chromatin-immunoprecipitation (ChIP) and reporter assays demonstrated that endogenous p53 protein would bind directly to the promoter region of the DUSP5 gene, implying p53-dependent transcriptional activity. Overexpression of DUSP5 suppressed the growth of several types of human cancer cells, in which Erk1/2 was significantly dephosphorylated. If, as the results suggest, DUSP5 is a direct target of p53, it represents a novel mechanism by which p53 might negatively regulate cell-cycle progression by downregulating mitogen- or stress-activated protein kinases.

MeSH terms

  • Apoptosis
  • Dual-Specificity Phosphatases
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protein Tyrosine Phosphatases / physiology*
  • Transcription, Genetic*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • Tumor Suppressor Protein p53
  • Mitogen-Activated Protein Kinases
  • DUSP5 protein, human
  • Dual-Specificity Phosphatases
  • Protein Tyrosine Phosphatases