Tumor viruses are useful tools for understanding mechanisms of cell transformation and carcinogenesis. We will study the mechanism of cell transformation by polyoma virus. The polyoma genome encodes three early proteins: the small, middle and large tumor antigens, which are responsible for tumorigenesis in vivo and oncogenic transformation in vitro. The middle tumor antigen (MTAg) plays a central role in transformation. It is located in cell membranes and is associated with a tyrosine-specific protein kinase activity which closely correlates with its ability to transform cells. MTAg associates with pp60c-src, the cellular homologue of the Rous sarcoma virus transforming protein, pp60c-src. pp60c-src has intrinsic protein kinase activity which is enhanced by its association with functional MTAg in polyoma virus-infected and transformed cells. MTAg-associated pp60c-src appears to have an unusual modification; an additional tyrosine phosphorylation site is present in the N-terminal portion of the molecule. These findings raise the intriguing possibility that MTAg may associate with, modify and activate the cellular proto-oncogene product, pp60c-src, enhancing its protein kinase activity. We propose to study the nature and function of the association between MTAg and pp60c-src, using three kinds of MT mounts: 1) mutants with deletions of N-terminal amino acid sequences, 2) a mutant with the C-terminus of the MTAg replaced by the C-terminus of the vesicular stomatitis virus glycoprotein G, 3) mutants with amino acid substitutions in the C-terminus which render the MTAg cold sensitive for the maintenance of transformation. Studies of MTAgs with altered N- and C-termini should help clarify the involvement of these regions of MTAg in pp60c-src association, modification and activation. Studies of the cold-sensitive MTAgs may implicate one or more of these functions in the process of cell transformation.
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