This study investigates the activation of mitogen-activated protein kinase (MAPK) pathways by hydrogen peroxide (H₂O₂) and its impact on cell survival following oxidant injury. The authors found that H₂O₂ rapidly and transiently activated extracellular signal-regulated protein kinase (ERK2) in various cell types, with a 10-20-fold increase in kinase activity within 10 minutes. H₂O₂ also moderately activated c-Jun N-terminal kinase and p38/RK/CSBP. The activation of ERK2 was blocked by pretreatment with Suramin, N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating the involvement of growth factor receptors and metal-catalyzed free radical formation. The study further demonstrated that the dominant negative Ras-N-17 allele reduced ERK2 activation and increased sensitivity to H₂O₂ toxicity in PC12 cells. In NIH 3T3 cells, constitutively active MEK increased resistance to H₂O₂, while kinase-defective MEK decreased it. These findings suggest that ERK2 plays a critical role in mediating cell survival following oxidant injury, and that modulation of the ERK pathway can significantly affect cellular response to oxidative stress.This study investigates the activation of mitogen-activated protein kinase (MAPK) pathways by hydrogen peroxide (H₂O₂) and its impact on cell survival following oxidant injury. The authors found that H₂O₂ rapidly and transiently activated extracellular signal-regulated protein kinase (ERK2) in various cell types, with a 10-20-fold increase in kinase activity within 10 minutes. H₂O₂ also moderately activated c-Jun N-terminal kinase and p38/RK/CSBP. The activation of ERK2 was blocked by pretreatment with Suramin, N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating the involvement of growth factor receptors and metal-catalyzed free radical formation. The study further demonstrated that the dominant negative Ras-N-17 allele reduced ERK2 activation and increased sensitivity to H₂O₂ toxicity in PC12 cells. In NIH 3T3 cells, constitutively active MEK increased resistance to H₂O₂, while kinase-defective MEK decreased it. These findings suggest that ERK2 plays a critical role in mediating cell survival following oxidant injury, and that modulation of the ERK pathway can significantly affect cellular response to oxidative stress.