The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death

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 (H(2)O(2)) induces MKP-1 and activates MAPKs. Induction of MKP-1 by H(2)O(2) correlated with inactivation of p38 and c-Jun-NH(2)-kinase (JNK). Overexpression of MKP-1 increased cell resistance to H(2)O(2)-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 H(2)O(2). More importantly, primary embryonic fibroblasts from mice lacking MKP-1 had a higher level of phosphorylated p38 and JNK and were more sensitive to H(2)O(2)-induced cell death compared with corresponding cells with MKP-1, indicating that p38 and JNK pathways may play important roles in H(2)O(2)-mediated cell death. Thus, these results suggest that activation of MKP-1 is a survival mechanism against oxidative damage.