Oxidative stress and DNA damage play a critical role in the development of degenerative diseases, and may underlie the aging process itself. Cells respond to such stresses with the induction of numerous gene products but little is known concerning the signal transduction pathways mediating these effects or the functional significance of the induced gene products. Recent evidence indicates that the signaling pathways mediating the cellular stress response overlap significantly with those regulating the response to mitogenic stimuli and involve one or more mitogen activated protein (MAP) kinase cascades. This project focuses on several topics aimed at increasing our understanding of basic mechanisms associated with the activation of gene expression to different forms of genotoxic stress and the consequences of the response. These include: (1) differential activation of various MAP kinases (ERK, JNK/SAPK and p38) in response to diverse genotoxic and growth arrest-inducing stresses including UVC irradiation, hydrogen peroxide, methyl methanesulfonate, sodium arsenite, prostaglandin A2 and phenylacetate; (2) the role of growth factor receptors and oxidant injury in sensing damage and triggering MAP kinase activation in response to different stresses; (3) mechanisms involved in attenuating the response; and (4) the relationships between these acute cellular responses and survival. In addition, we are investigating the response to genotoxic stress as a function of aging using primary hepatocytes derived from young and aged animals as a model. We have provided evidence that ERK MAP kinase activation in response to both mitogenic stimulation and genotoxic stress declines with aging and are exploring the mechanisms contributing to this decline.
