Exposure of the skin to ultraviolet radiation and to environmental toxic compounds that produce oxidative damage have numerous negative health consequences, among which the development of skin cancer is one of the most serious. The mechanisms by which these agents interact with the epidermis and by which the epidermal cells respond to damage are incompletely understood. Of crucial interest is the identity of cellular molecules that sense damage from environmental stressors, the intracellular signaling pathways by which the damage is conveyed, and the mechanisms that determine how cells choose between survival and death. During the previous grant cycle the applicant identified the 28S rRNA of ribosomes as a molecular sensor for stress induced by ultraviolet B radiation and other toxic molecules. Signals from ribosomes are quickly conveyed through pathways that activate the stress-activated protein kinases (SAPK) and appear to be involved in many of the crucial pathways that determine survival or apoptosis. Agents that produce oxidative damage do not mediate stress signals via 28S rRNA, and neither ultraviolet B or C radiation activates the SAPK (JNK and p38 MAPK) by inducing oxidative stress in cells. Recently the applicants have discovered that in primary normal keratinocytes the activation of the SAPK cascade by either arsenite, an oxidative stressor, or ultraviolet B radiation leads to an immediate and coordinate dephosphorylation and inactivation of ERK, a kinase family member that appears to be involved in regulation of cell proliferation and survival. The applicants' evidence indicates that the rapid dephosphorylation of ERK results from a stress-induced activation of a pre-existing phosphatase.
The aims of this renewal application are to identify in keratinocytes the phosphatase responsible for the dephosphorylation of ERK in response to ultraviolet B radiation and arsenite and to identify the mode of regulation of the stress-activated ERK phosphatase. The applicants will also determine whether members of the SAPK signaling cascade are responsible for the activation of the ERK phosphatase. Finally, they propose to elucidate the roles of JNK, p38 MAP, and ERK in apoptotic and prosurvival responses of human keratinocytes to ultraviolet B radiation and oxidative stress.
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