Mutations in oncogenes and tumor suppressor genes in animal and human tumors may give important clues as to the exposures that led to the tumors. For rodent neoplasms that are pathologically similar to the corresponding human cancer, the rodent disease may be used to model the cellular events involved and to study prevention and therapy. Currently, we are focusing on the von Hippel-Lindau ( VHL) gene in kidney cancer, and the K- ras gene in lung cancer. The VHL tumor suppressor gene is mutated in a high percentage of both familial and sporadic renal cell carcinomas. We have recently established an animal model for causation of VHL mutations in clear cell renal tumors, by the environmental carcinogen N-nitrosodimethylamine. In addition, we have found that VHL is down-regulated in several other types of kidney cancer in animal models. Investigation of the effects of altered VHL amounts or activities is currently involving microarrays, and transfection of the gene into kidney cells. In studies of the role of the oncogene K- ras in genesis of adenocarcinoma of the lung, we are utilizing a mouse model, including tumors induced in vivo, and normal immortalized and transformed alveolar type 2 cells in vitro. We are pursuing several novel hypotheses: that K- ras is actually a tumor suppressor gene, controlling growth and/or differentiation; that mutant K-ras generates reactive oxygen which leads to tumor initiation; and that N-ras may have a role in cell proliferation in lung cells. Failure of p53-dependent cell cycle arrest after carcinogen exposure is also under investigation.
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