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DUSP1 is controlled by p53 during the cellular response to oxidative stress
Author(s) -
Liu Yuxin,
Wang Jianli,
Yin Yuxin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.648.28
Subject(s) - phosphatase , microbiology and biotechnology , kinase , dephosphorylation , apoptosis , protein kinase a , oxidative stress , dual specificity phosphatase , biology , phosphorylation , chemistry , biochemistry
p53 controls the cellular response to genotoxic stress through multiple mechanisms. We report here that p53 regulates DUSP1, a dual‐specific threonine and tyrosine phosphatase with stringent substrate specificity for MAP kinase. DUSP1 is a potent inhibitor of MAK kinase activity through dephosphorylation of MAPK. In a colon cancer cell line containing inducible ectopic p53, DUSP1 protein level is significantly increased upon activation of p53, leading to cell death in response to nutritional stress. In MEF cells, DUSP1 protein abundance is greatly increased following oxidative stress in a p53‐ dependent manner, also when apoptosis is triggered. We show that p53 induces the activity of a human DUSP1 regulatory region. Furthermore, p53 can physically interact with the DUSP1 regulatory region in vivo and p53 binds to a 10‐bp perfect palindromic site in this DUSP1 regulatory region. We demonstrate that overexpression of DUSP1 or inhibition of MAK kinase activity significantly increases cellular susceptibility to oxidative damage. Those findings indicate that p53 is a transcriptional regulator of DUSP1 in stress responses. Our results reveal a mechanism whereby p53 selectively regulates target genes, and suggest a way in which subgroups of those target genes might be controlled independently.