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DNA Damage and Cellular Stress Responses

DUSP1 Is Controlled by p53 during the Cellular Response to Oxidative Stress

¹ Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons and ² Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York and ³ Department of Hematology, Second Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, P.R. China

Requests for reprints: Yuxin Yin, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032. Phone: 212-305-5699; Fax: 212-305-3229. E-mail: yy151{at}columbia.edu

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 mitogen-activated protein kinase (MAPK). DUSP1 is a potent inhibitor of MAPK 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 mouse embryo fibroblast cells, DUSP1 protein abundance is greatly increased after oxidative stress in a p53-dependent manner and 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 show that overexpression of DUSP1 or inhibition of MAPK activity significantly increases cellular susceptibility to oxidative damage. These 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. (Mol Cancer Res 2008;6(4):624–33)