Ultraviolet (UV) radiation from the sun is the main causative agent in the formation of non-melanoma skin cancer, by far the most frequent type of cancer in the United States. In addition, the risk for exposure to harmful UVB radiation is rising with the continued destruction of the protective atmospheric ozone layer. The induction of programmed cell death, or apoptosis, is a major cellular protective mechanism for keratinocytes exposed to mutagenic doses of UV radiation. Indeed, the inactivation of tumor suppressor genes involved in mediated the UV apoptotic and cell cycle checkpoint responses enhance skin tumor formation. A long-term goal of this proposal is to elucidate the death effector pathways activated by UV radiation in human keratinocytes, and to determine how these pathways become altered during multi-stage skin carcinogenesis. We have shown that the induction of apoptosis by UV radiation involves activation of protein kinase C (PKC) 8, however PKC8 is often inactivated for down-regulated in neoplastic keratinocytes, making it a potential tumor suppressor gene. To determine the role of PKC8 in the apoptotic response and transformation of keratinocytes exposed to UV, we propose to 1) Characterize the mechanism(s) of PKC8 loss in human squamous cell carcinomas and which additional oncogene/tumor suppressor alterations accompany PKC8 loss; 2) Determine the mechanism by which the PKC8 catalytic fragment triggers apoptosis; 3) Determine the role of PKC8 loss in keratinocyte transformation by performing UV carcinogenesis experiments with PKC8 null mice, and by introducing defined genetic elements into human keratinocytes with suppressed PKC5 expression. These studies will help define the molecular mechanisms involved in human skin carcinogenesis, and may identify molecular targets for preventive or therapeutic interventions. These studies will also enhance our understanding of basic apoptotic signaling pathways relevant to many normal and disease processes. ? ? ?
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