Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation

Oxidative stress is known to induce apoptosis in a wide variety of cell types, apparently by modulating intracellular signaling pathways. High concentrations of H₂O₂ have been found to induce apoptosis in L929 mouse fibroblast cells. To elucidate the mechanisms of H ₂O₂-mediated apoptosis, ERK1/2, p38-MAPK, and JNK1/2 phosphorylation was examined, and ERK1/2 and JNK1/2 were found to be activated by H₂O₂. Inhibition of ERK1/2 activation by treatment of L929 cells with PD98059 or dominant-negative ERK2 transfection blocked H ₂O₂-induced apoptosis, while inhibition of JNK1/2 by dominant-negative JNK1 or JNK2 or MKK4 or MKK7 transfection did not affect H₂O₂-mediated apoptosis. H₂O ₂-mediated ERK1/2 activation was not only Ras-Raf dependent, but also both tyrosine kinase (PDGFβ receptor and Src) and PKCδ dependent. H₂O₂-mediated PKCδ-dependent and tyrosine kinase-dependent ERK1/2 activations were independent from each other. Based on the above results, we suggest for the first time that oxidative damage-induced apoptosis is mediated by ERK1/2 phosphorylation which is not only Ras-Raf dependent, but also both tyrosine kinase and PKCδ dependent.