Abstract : Oxidative stress is known to induce cell death in a wide variety of cell types, apparently by modulating intracellular signaling pathways. In this study, we have examined the activation of mitogen‐activated protein kinase (MAPK) cascades in relation to oxidant‐induced cell death in an oligodendrocyte cell line, central glia‐4 (CG4). Exposure of CG4 cells to hydrogen peroxide (H2O2) resulted in an increased tyrosine phosphorylation of several protein species, including the abundantly expressed platelet‐derived growth factor (PDGF) receptor and the activation of the three MAPK subgroups, i.e., extracellular signal‐regulated kinase (ERK), p38 MAPK, and c‐Jun N‐terminal kinase (JNK). Dose‐response studies showed differential sensitivities of PDGF receptor phosphorylation (>1 mM) and ERK/p38 MAPK (>0.5 mM) and JNK (>0.1 mM) activation by H2O2. The activation of ERK was inhibited by PD98059, a specific inhibitor of the upstream kinase, MAPK or ERK kinase (MEK). H2O2 also activated MAPK‐activated protein kinase‐2, and this activation was blocked by SB203580, a specific inhibitor of p38 MAPK. The oxidant‐induced cell death was indicated by morphological changes, decreased 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide reduction, and DNA fragmentation. These effects were suppressed dose‐dependently by the MEK inhibitor PD98059. The results demonstrate that H2O2 induces the activation of multiple MAPKs in oligodendrocyte progenitors and that the activation of ERK is associated with oxidant‐mediated cytotoxicity.
Journal of Neurochemistry – Wiley
Published: Jan 1, 1999
Keywords: ; ; ; ; ;
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