The main goal of this proposal is to find new transforming genes which may be involved human neoplasia. This search is based on the use of an animal model system for carcinogenesis which uses chemical and physical carcinogens both in vivo and in vitro to generate Syrian hamster cells with diverse levels of malignant transformation and tumorigenicity. Experiments will be done to determine the nature of the transforming genes in hamster transformed cells, with emphasis on oncogenes and proto-oncogenes not described to date. Comparative studies between the novel oncogenes and their proto-oncogenes will provide information on the mechanism of activation which will also be analyzed in relation to the known mutational activity of the carcinogen. The working hypothesis of this proposal of this proposal predicts that one can exploit the species-specific differences between hamster and human cells, with regard to their response to carcinogenic insults, to detect oncogenes that remain undetectable in most human tumors or tumor cell lines. The hypothesis is based on the assumption that the proximity between hamster and mouse cellular backgrounds will allow the detection in NIH/3T3 cells, or nude mice, of cases of malignant alteration of proto-oncogenes that would remain undetectable if they had occurred in a human cellular background. Preliminary results by the PI involving the identification of a new oncogene strongly support the soundness of this hypothesis, and clearly encourage its further testing. The research plan has four areas. (1) A new oncogene already identified using the Syrian hamster transformation model will be molecularly cloned by cosmid-rescue or other methods, and its normal oncogene will also be isolated. (2) Comparative studies between the new oncogene and its normal counterpart will be performed, placing special emphasis on efforts to characterize the transforming activity of the oncogene and the transforming potential of the proto-oncogene on different cell types. (3) Human tumors and tumor cell lines will be screened for the presence of the oncogene homologous to the new hamster transforming gene, to determine its possible cases of human neoplasia. (4) The presence of active oncogenes in other carcinogen-initiated hamster cell lines will be studied following similar experimental schemes to the ones used to find the new hamster oncogene.
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