Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53.
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.
Ueda
Koji
K
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Arakawa
Hirofumi
H
Nakamura
Yusuke
Y
D017209:Apoptosis; D054637:Dual-Specificity Phosphatases; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; C442320:DUSP5 protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases