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

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Abstract
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)