This application seeks to continue the progress made in analysis of oncogenes activated in a well-defined experimental tumor model system. The novel oncogenes that were previously identified as being activated in rat nasal squamous carcinomas induced by inhalation of methylmethane sulfonate, dimethylcarbamyl chloride, and beta-propiolactone will be further characterized after molecular cloning of the genes. Alternative cloning strategies will include ligation or cotransfection of marker sequences such as genes for amber mutation suppression or antibiotic resistance. Once the novel nasal tumor oncogenes have been cloned, they will be characterized by DNA sequence analysis and their chromosomal location, levels of expression in various tissues and mechanism(s) of activation will be investigated. The importance of tissue as well as carcinogen specificity in oncogene activation, and the issue of oncogene activation as a function of neoplastic progression in an animal tumor model will be addressed. Chemical carcinogens known to induce malignant and benign tumors of several histologic types in the nasal cavity after exposure by inhalation will be used to generate panels of tumors. Activated oncogenes in these tumors will be identified by the NIH3T3 transfection or the cotransfection/nude mouse tumorigenesis assays, followed by Southern blot hybridization analysis. The hypothesis that certain oncogenes are actively involved in cellular transformation of particular tissue types and not others will be tested by transfecting purified oncogenes into cultures of epithelial cells. Increased understanding of the molecular mechanisms by which certain genes are activated in specific cell types during progression to malignancy and the relationship between carcinogenic etiology and such oncogene will contribute to knowledge of the nature of environmental carcinogenesis in animals and man, and will aid in the development of strategies for prevention, intervention or protection against cancer for exposed or susceptible populations.
Showing the most recent 10 out of 14 publications
