In the experimental model of mouse skin carcinogenesis we and other have shown that ionizing radiation can act as a weak initiating agent, a complete carcinogen and an agent effective in inducing the progression of benign to malignant skin tumors. In this skin model, ionizing radiation can induce squamous cell carcinomas (SCCs), basal cell carcinomas (BSSs) and fibrosarcomas. My laboratory has demonstrated the presence of distinct non-ras transforming gene(s) in X-ray initiated SCCs and differential expression of certain """"""""tumor associated"""""""" genes in different histologies of X-ray induced mouse skin tumors. The goal of the proposed research is to extend our initial studies and test the following hypotheses. The first hypothesis states that the enhanced conversion of benign to malignant mouse skin tumors induced by ionizing radiation is a direct, inductive effect on benign papilloma cells. The second hypothesis states that malignant transformation of mouse epidermal basal cells.
The specific aims to be treatment of cloned benign papilloma cells growing in cell culture leads to a clone distinct non-ras transforming genes present in ionizing radiation induced SCCs. The cloning strategy will involve the experimental linkage of the transforming gene(s) to an supF fragment as a molecular and biological """"""""tag"""""""" to trace the transforming gene during multiple rounds of transfection. 3) to detect and then identify transforming gene(s) or other cellular genes that are differentially expressed in ionizing radiation induced mouse skin BCCs. Two different approaches will be taken to identify transforming genes. The first is to utilize the NIH3T3 cotransfection, nude mouse tumor genomic transfection and the detection of anchorage independent growth. A third approach to identify critical cellular genes is the use of subtractive hybridization to identify genes that are differentially expressed in the progression of basal cells to BCCs. A better understanding of the molecular mechanisms of radiation carcinogenesis would aid in identifying groups of individuals at high risk of radiation carcinogenesis and potential approaches for intervention in groups of people unavoidably exposed to ionizing radiation.
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