Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases

To elucidate mechanisms underlying glutathione S-transferase p (GSTp)-media ted cellular protection against oxidative stress-induced cell death, the ef fect of GSTp on stress signaling pathways was investigated before and after H2O2 treatment. Under nonstressed conditions, increased expression of GSTp via a tet-off-inducible GSTp in NIH 3T3 cells increased the phosphorylatio n of mitogen-activated protein (MAP) kinase kinase 4, p38, extracellular re ceptor kinase (ERK), and inhibitor of kappa-kinase (IKK), and reduced phosp horylation of MAP kinase kinase 7 and Jun NH2-terminal kinase (JNK). Wherea s H2O2 treatment of cells induced JNK, p38, and IKK activities, in the pres ence of H2O2 and elevated GSTp expression there was an additional increase in ERK, p38, and IKK activities and a decrease in JNK activity. GSTp-mediat ed protection from H2O2-induced death was attenuated upon inhibition of p38 , nuclear factor kappa B, or MAP kinase by dominant negative or pharmacolog ical inhibitors. Conversely, expression of a dominant negative JNK protecte d cells from H2O2-mediated death. These data suggest that the coordinated r egulation of stress kinases by GSTp, as reflected by increased p38, ERK, an d nuclear factor kappa B activities together with suppression of JNK signal ing, contributes to protection of cells against reactive oxygen species-med iated death.