SUSCEPTIBILITY DETERMINANTS FOR PHOTOCARCINOGENESIS

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Ultraviolet radiation in sunlight is the major cause of skin cancer in humans. However, individuals differ considerably in their susceptibility to cancer of the skin as well as cancer in other organs. The goal of this project is to understand the molecular mechanisms involved in determining susceptibility to photocarcinogenesis. The mouse skin model will be used in order to take advantage of the variety of mouse stocks and strains with documented differences in susceptibility to physical as well as chemical skin carcinogenesis. The overall theme of the project is to elucidate the mechanisms that cause some mouse strains or stocks to be highly susceptible to photocarcinogenesis, and others to be relatively resistant. The two general areas to be investigated are 1) molecular regulation of cell proliferation and differentiation in murine skin, and 2) repair of genotoxic photoproducts from the murine genome. Regulation of cell growth in the epidermis will be investigated in organ cultures of mouse skin explants in order to use in vitro experimental techniques without compromising tissue architecture. Organ cultures of normal and perturbed (UV- irradiated) epidermal tissue will be used to examine the regulation of epidermal proliferation and differentiation by exogenous growth factors/modulators in the culture media. Repair of DNA photoproducts in the murine genome will be investigated to identify regions of preferential (hyperactive) repair and to measure repair in specific genes involved in tissue regeneration and neoplastic transformation. The distribution of photoproduct repair in restriction fragments of DNA fractionated by gel electrophoresis will be examined using monoclonal antibodies specific for DNA photoproducts. Repair of photoproducts in specific genes, particularly oncogenes, will be examined by Southern Blot analysis of DNA subjected to damage- specific cleavage by T4 endonuclease V and restriction enzyme digestion. These experiments will provide information critical to our understanding of the molecular basis for susceptibility to photocarcinogenesis. In addition, this knowledge may provide insights into 1) the nature of susceptibility determinants for chemical carcinogenesis, and 2) the relationship between tissue regeneration and cancer.