The overall goal of this research is to determine whether alterations in the expression of specific tumor associated genes (myc, fos, jun, transin) are responsible for the radiation-induced conversion of benign papillomas to malignant carcinomas in mouse skin carcinogenesis and to determine whether this conversion to malignancy can be inhibited by protease inhibitors as a result of an alteration in the expression of the tumor associated genes. The following specific areas of experimentation will be involved: 1. Compare the expression pattern of tumor associated genes in normal and carcinogen-treated tissue as well as in benign and malignant mouse skin tumors that have been promoted by ionizing radiation. Expression levels of the myc, fos, and jun genes will be determined as a function of tumor progression. 2. Determine the effect of protease inhibitors on the expression of the myc, fos, and jun genes in normal and carcinogen-treated mouse epidermis. 3. Examine the effect of protease inhibitors on the conversion of radiation-induced mouse skin papillomas to malignant carcinomas. 4. Measure levels of expression of the transin protease gene at different stages in the progression of radiation carcinogenesis and determine whether these levels are modulated by protease inhibitors in the mouse skin model. The results of these experiments should help to elucidate the mechanism(s) involved in the progression of mouse skin carcinogenesis brought about by exposure to ionizing radiation.
