The goals of this project are to define the pathways of induction of tumors in the mouse by polyoma virus at the molecular level. To this end, mutant strains of virus that have been well characterized in cell culture systems will be inoculated into newborn mice; the latter will then be followed for development of the various tumor types which the wild-type virus is known to induce. Site- directed mutagenesis will be used to modify particular regions of the middle T viral oncogene. These mutants will then be characterized biochemically and in cell transformation assays in order to understand more fully the interactions of middle T with cellular enzymes, including the tyrosine protein kinase pp60c-src, phosphatidylinositol 3-kinase and protein phosphatase 2A. Analogues of inositol modified at the 3-position will be examined as potential inhibitors of 3-phosphoinositide metabolism in vivo. Mutants of large T, or other viral proteins potentially involved in interactions with host tumor suppressor genes, will be sought and characterized. Cellular kinases that phosphorylate the major viral capsid protein VP1 will be identified. Attempts will be made to identify additional cellular elements involved in a cascade between middle T and VP1; this cascade is viewed as overlapping with a mitogenic pathway of the host cell. Finally, an attempt will be made to identify, map, and ultimately clone, genes of the host that confer susceptibility or resistance to tumor induction by the virus.
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