Age-related changes in activation of mitogen-activated protein kinase cascades by oxidative stress.

Oxidative stress is thought to play a critical role in aging and the pathogenesis of human disease. Molecular studies of both the physiologic function of oxidants and the deleterious consequences of exposure to oxidative stress have suggested that signal transduction cascades may be targeted by oxidants. Here, we review recent studies from this laboratory examining the molecular basis for the activation of mitogen-activated protein kinases by oxidative stress and the influence of these pathways on cellular fate. We examine the association between constitutive activation of extracellular signal-regulated kinase (ERK) and cancer, and discuss how such mechanisms may contribute to oxidant-induced skin carcinogenesis. We also address the relationship between a decline in activation of this same pathway and the aged phenotype. In this regard, we review evidence that a decrease in activation of ERK by growth factor correlates with a reduced proliferative capacity in the isolated rat hepatocyte model, and we provide new data indicating that the activation of the ERK pathway in response to oxidant stimuli is also decreased with age. Further evidence demonstrates that this alteration is associated with both a reduced mitogenic response and a decline in hepatocyte cell survival in response to oxidative stress. Finally, we provide perspective on how modulations in ERK signaling may interplay with other changes in signal transduction cascades in the aging process.