ROLE OF P53 IN UV IMMUNE SUPPRESSION AND CARCINOGENESIS

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Skin cancers induced in inbred mice by chronic UN irradiation are highly antigenic and exhibit a high frequency of p53 mutations. In this model, cancer induction by UV radiation is accompanied by suppression of the immune response against these skin cancers, and the immune suppression plays an essential role in skin cancer growth and pathogenesis. Recent studies indicate the UV-induced DNA damage is the primary event that initiates immunosuppression. Because p53 plays a pivotal role in the response to and repair of DNA damage, this gene may serve as an essential control point in the pathway leading to UV-induced immune suppression, in addition to playing a role in the process of neoplastic transformation. Furthermore, mutant p53 protein could contribute to the unusual antigenic properties exhibited by UV-induced tumors. To test these hypotheses, p 53 knock out mice, in which one or both copies of th p53 gene have been inactivated by homologous recombination, will be exposed to UV radiation and tested for susceptibility to UV-induced suppression of cell-mediated immunity and induction of immunosuppressive epidermal cytokines. The role of p53 in UV carcinogenesis will be assessed by comparing tumor induction in +/+, +/-, and -/- mice on a C57BL/6 genetic background. To determine whether mutant p53 protein serves as a transplantation antigen on UV-induced tumors, the antigenic properties of tumors induced in +/+, +/-, and -/- mice will be compared. If athe tumors induced in p53 null mice do not express UV-associated tumor antigens, these tumors will be used as recipients for transfection of mutated p53, to determine whether introduction and expression of mutated p53 confers on these cells the unusual antigenic characteristics of UV-induced skin cancers.