Exposure of mammalian cells or skin to ultraviolet (UV) radiation in DNA damage and induction of a stress response called the UV response. This induction response is mediated by several transcription factors, including AP-1, NF-kB and p53. Only p53 is likely to be directly induced in response to UV-damaged DNA. AP-1 and NF-kB, on the other hand, are activated through signal transduction cascades that appear to be elicited by effects of short wavelength UV on the cell surface, independently of DNA damage. Both pathways rely on specific signal-responsive protein kinases. The protein kinases that stimulate AP-1 activity in response to UV irradiation are JNK and p38. The protein kinase involved in NF-kB activation has not been molecularly identified. As it phosphorylates the IkB inhibitors of NF-kB, we refer to it as the IkB kinase. We propose to further investigate the mechanism by which exposure to UV leads to activation of JNK, p38 and the IkB kinase by establishing a cell-free system in which these kinases can be activated by UV. We also plan to molecularly clone the UV responsive IkB kinase and study its activation mechanism. Most importantly, however, our studies will focus on the physiological roles of these protein kinases in the response of mammalian cells to UV radiation, especially their potential involvement in protection against UV damage. This aspect of the UV response is the least well understood. Activation of AP-1 and NF-kB have both been proposed to be involved in diverse and conflicting responses including apoptosis, tumor promotion, protection against radiation induced damage and aging. As UV light is a common carcinogen and genotoxic agent to which we are exposed, understanding the function of UV activated protein kinases is of great physiological and clinical importance. Using fibroblasts and T cells derived from knockout mice that are deficient in critical components of AP-1 and NF-kB activation we will investigate whether these pathways are protective or damaging. We also plan to identify genes that are specifically induced in response to JNK and c-Jun activation by UV radiation. These studies should shed new light on the mechanisms underlying cellular responses to UV radiation. These studies will also contribute to understanding how cells respond to other forms of radiation.
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