Changes in the structure and function of normal cellular genes lie at the heart of carcinogenesis. The work supported by this grant seeks to identify cellular genes responsible for cancerous growth, the means by which carcinogens bring these genes into play, and the biochemical mechanisms by which the genes act. If the search succeeds, it should provide new and more rational strategies for the prevention, diagnosis and therapy of cancer; and it should also reveal principles by which the normal growth and development of cells are controlled. The work is conducted primarily with retroviruses, whose tumorigenic potentials represent a microcosm of carcinogenesis. Some of these viruses carry """"""""oncogenes"""""""" that directly convert cells to neoplastic growth. Other retroviruses do not possess oncogenes but instead induce tumors by mutating the DNA of host cells. Both forms of tumorigenesis by retroviruses offer access to cellular genes that may contribute to neoplastic growth: the oncogene of retroviruses are partial or complete copies of normal cellular genes (""""""""proto-oncogenes""""""""), tranduced into the viruses by accident during the course of evolution; and the mutagenesis of cellular DNA by retroviruses activates genes that can also be regarded as proto-oncogenes. A suite of avian retroviruses is used that, in the aggregate, provides experimental models for most of the major forms of cancer. Among these viruses are represented five oncogenes (v-src, v-fps, v-myc, v-erb-B, and v-myb) that are major objects of study. Experimental strategies are aimed at identifying the proteins encoded by oncogenes and proto-oncogenes; determining the functions of these proteins in their normal guise; discerning changes in their function that may account for tumorigenesis; identifying cellular functions whose perversion by oncogenes are involved in the genesis of human tumors; and exploiting the discovery of proto-oncogenes to perform genetic and biochemical analyses of how the growth and differentiation of normal cells is controlled. Methods include molecular cloning; nucleotide sequencing; DNA-mediated gene transfer; preparation of both polyclonal and monoclonal antibodies; immunoprecipitation; immunofluorescence and electron microscopy; purification and chemical analysis of proteins; site-directed mutagenesis with recombinant; and genetic analyses with both Drosophila melanogaster and Saccharomyces cerevisiae.
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