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The Role of Mitogen-Activated Protein Kinase Phosphatase-1 in Oxidative Damage–Induced Cell Death

¹ Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan and ² Children's Research Institute, Department of Pediatrics, The Ohio State University, Columbus, Ohio

Requests for reprints: Gen Sheng Wu, Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Room E216, 110 East Warren Avenue, Detroit, MI 48201. Phone: 313-833-0715, ext. 2328; Fax: 313-831-7518; E-mail: wug{at}karmanos.org.

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a member of the MAPK phosphatase family that functions as a negative regulator of MAPK signaling. MKP-1 is induced by oxidative stress, but the role of its induction in cell death is not fully understood. Here, we show that hydrogen peroxide (H₂O₂) induces MKP-1 and activates MAPKs. Induction of MKP-1 by H₂O₂ correlated with inactivation of p38 and c-Jun-NH₂-kinase (JNK). Overexpression of MKP-1 increased cell resistance to H₂O₂-induced death. Furthermore, we show by small interfering RNA silencing that down-regulation of MKP-1 increases phosphorylated p38 and JNK and subsequent cell death induced by H₂O₂. More importantly, primary embryonic fibroblasts from mice lacking MKP-1 had a higher level of phosphorylated p38 and JNK and were more sensitive to H₂O₂-induced cell death compared with corresponding cells with MKP-1, indicating that p38 and JNK pathways may play important roles in H₂O₂-mediated cell death. Thus, these results suggest that activation of MKP-1 is a survival mechanism against oxidative damage. (Cancer Res 2006; 66(9): 4888-94)

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