Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a member of the mitogen-activated protein kinase (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 elusive. Here we demonstrate that MKP-1 induction by H2O2 is a survival mechanism against oxidative damage. We show that H2O2 induces both MKP-1 and activation of MAP kinases. Induction of MKP-1 by H2O2 correlated with inactivation of p38 and JNK. Overexpression of MKP-1 increased cell resistance to H2O2-induced death. Furthermore, we show by siRNA 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 to corresponding cells with MKP-1, suggesting that p38 and JNK pathways play important roles in H2O2-mediated cell death. Collectively, these results establish a critical role of p38 and JNK pathways in oxidative damage-mediated cell death and suggest that activation of MKP-1 signaling is a survival mechanism against oxidative damage (Supported by NIH/NCI grant CA100073-01 A1).

[Proc Amer Assoc Cancer Res, Volume 47, 2006]