p38^MAPK inhibits Ras-dependent activation of mitogen-activated protein kinase kinase-1 in oxidative stress signaling

Reactive oxygen species (ROS) block proliferation and can cause apoptosis in smooth muscle cells (SMCs). The purpose of the present study is to investigate the mechanisms underlying these effects of ROS. We demonstrate that p38^MAPK induced by the ROS pervanadate (PV), a 1:1 mixture of vanadate and H₂O₂, inhibits the activation of Mitogen-activated protein kinase-1 (MEK1). The effect of PV on MEK1 is dependent on the concentration used. Up to 10 μM, it is activatory, but higher doses fail to stimulate MEK1. This loss of MEK1 activity is paralleled by an induction of p38^MAPK and can be partially prevented by the addition of the p38^MAPK inhibitor, SB203580. PV also blocks MEK1 activation by PDGF-BB, a potent mitogen in cultured SMCs. This effect appears to be mediated by an inhibition of Ras. Both PDGF-BB-induced Ras and MEK1 activation are preserved in the presence of PV by the addition of SB203580. We speculate that p38^MAPK induced by stress signals inhibits Ras activation, thereby blocking growth and survival pathways.