This Program proposes to continue its interactive efforts aimed at elucidating the central molecular mechanisms which underlie the transformation of cultured cells and the development of a broad array of malignant tumors by the papova/papilloma families of DNA tumor viruses. During the past grant period, progress was made in understanding certain key events in the biochemical function of SV40 and PY large T Ag, PY mT and st Ags, as well as BPV and HPV E6. Among the most surprising discoveries made in this program was that the N-terminal SV40 and PY T Ag common region(s) are DNA J domains which support both the replicative and elements of the transforming properties of these viruses. Moreover, fresh insights into the degree of complexity of PY tumorigenesis emerged from studies of the behavior of PY mT mutants defective in the binding of selected signaling proteins. In the next grant period, we propose to continue to work across a wide spectrum of complementary approaches, Our goal is to take advantage of extraordinary, new opportunities for drawing a more detailed and comprehensive picture of the major biochemical links connecting T, mT, St, and E6 biochemical function to key cellular perturbations that result in the evolution of a fully transformed and tumorigenic phenotype. The overriding goal of this work is to define the relationships between papovaviral transforming mechanisms and those processes which -give rise to spontaneous human neoplasms.
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