Our laboratory's research goal is to gain greater understanding of the molecular mechanisms that function during the tumorigenic process initiated by chemicals or environmental insults. To accomplish this goal we have exploited a transgenic mouse line called Tg.AC. Tg.AC mice were engineered to contain a v-Ha-ras oncogene, whose function has been found to be associated or causal of a majority of epithelial tumors in humans. Tg.AC transgenic mice produce skin papillomas when wounded, topically treated with chemical carcinogens, or exposed to ultraviolet radiation. They do not produce tumors when treated with non-carcinogens. As a result of this unique phenotype, the Tg.AC mouse model is being evaluated by the National Toxicology Program (NTP) as an adjunct to the conventional two-year bioassay for the identification of carcinogens. To aid in this evaluation we have developed assays to genotype the breeders of Tg.AC mice to ensure responsiveness. In addition, we have molecularly characterized the transgene's role in the tumorigenic response. To understand the regulation of gene expression we have mapped the promoter and potential transcription factors and their binding sites. We have cloned and sequenced the integration site on mouse chromosome 11. Recent data from our laboratory indicate that the transgene is integrated in a novel gene. We have identified this gene and are investigating the expression and regulatory role it may have in regulating of the transgene. We are also exploiting the ras dependent tumorigenic response of Tg.AC mice in genetic approaches in an attempt to understand the signaling pathways important for tumorigenesis. We have found that mice deficient in KSR (Kinase Suppressor of Ras) , a gene product required for EGFr mediated signaling. When KSR deficient mice are crossed to Tg.AC mice the TPA dependant tumorigenic response is blocked. This data indicate that the EGFr/ras/KSR signaling pathway is very important in Tg.AC tumorigenesis. Lastly, we continue to use the gene array technology to identify new genes that play significant roles ras mediated tumorigenesis.
