The long term, overall goal of this research program is to elucidate the mechanisms by which specific oncogenes contribute to the subversion of a cell from normal growth to oncogenically transformed behavior, as occurs in human cancer. Oncogene function will be investigated at the molecular, cellular and whole organism level using mammalian cells, animal viruses, the fruit fly and yeast as experimental systems. The research emphasis of component projects are as follow: Subproject 1. Shenk will study the function of the adenovirus type 5 E1B-55kDa and E1B- 19kDa oncoproteins during lytic viral growth and transformation, and he will examine the role of the adenovirus type 9 E1A oncogene in the induction of estrogen-dependent mammary tumors. Subproject 2. Broach will investigate the ras and ceremide signal transduction systems in Saccharomyces, both of which are homologous to signal transduction pathways in mammalian cells; he will study the mechanisms by which signals impinge on the pathways, probe the interactions of pathway components, and identify their downstream targets. Subproject 3. Schupbach will analyze the signal transduction pathway of the torpedo gene, the Drosophila homolog of the EGF tyrosine kinase receptor, delineating the molecular mechanisms by which torpedo is activated during oogenesis and the responses to the tyrosine kinase in follicle cells. Subproject 4. Levine and Wieschaus will study the human and Drosophila adenomatous polyposis coli (APC) genes, defining the normal cellular function of APC and the nature of its interaction with the Wnt-1 signalling pathway in both mammalian and invertebrate cells. Subproject 5. Levine will study the cellular mdm-2 oncogene, evaluating its ability to transform cells in the absence of p53, the normal regulation of the mdm-2 gene and its regulation after exposure to ultraviolet light, its possible role as an RNA-binding protein and searching for cellular proteins with which the Mdm-2 protein interacts.
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