This is a revised application for renewal of an ongoing project whose goal is to determine the mechanisms and physiological functions of radiation activated stress responses in mammals. We will continue to study signaling and gene expression responses that are activated by short wavelength ultraviolet (UV) radiation, a most common environmental carcinogen. The proposed research will focus on the regulation and function of the JNK and p38 MAP kinase (MAPK) cascades that are strongly activated by UV exposure. Both of these cascades lead to induction of c-Jun, a component of transcription factor AP-1 We found that c-Jun induction, a hallmark of the mammalian UV response, is required for allowing UV irradiated mouse fibroblasts to return to the cell cycle. This function is accomplished via interference with p53-mediated transcriptional activation through an unknown mechanism. During the next project period we plan to examine whether c-Jun and JNK exert a similar function in another cell type that is a target for UV induced carcinogenesis - the epidermal keratinocyte - and will continue to study the mechanism by which c-Jun suppresses p53 transcriptional activity. We will also investigate the role of p38 MAPK activation in modulating the outcome of UV exposure in mouse fibroblasts and will compare the mechanisms by which p38 affects cell cycle progression in UV irradiated cells to those that are used by JNK and c-Jun. In addition we will continue to elucidate the mechanisms responsible for activation of SNK and the closely related p38 MAPKs in response to UV radiation. The latter will be examined through a functional genomic approach based on the use of interfering RNA (RNAi) to systematically ablate the expression of genes coding for MAPK kinase kinases (MAPKKKs). This will allow us to identify the MAPKKK that mediates JNK and p38 activation by UV. The in vivo analysis of JNK and c-Jun function will be addressed through a reversed genetic approach based on conditional gene targeting in mice, that will allow us to abolish the expression of these proteins in a cell type specific manner without compromising animal viability.
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