Our long-term objective is to understand cell transformation by DNA tumor viruses. The transforming proteins of these viruses exert their effects, at least in part, by associating with cellular proteins involved in growth regulation. We will study nature and functional consequences of the association of the polyoma middle T antigen (mT) with protein phosphatase 2A (PP2A), pp60c-src and phosphatidylinositol-3 (PI-3) kinase, using a combination of genetic analysis of mT and biochemical analysis of cellular growth control signalling pathways. We will study mechanisms by which mT transactivates cellular growth control genes, including c-fos and c-jun, and will explore the involvement of ras and raf in mT-mediated transactivation and cell transformation. Neuroblastoma cells express a neuronal form of pp60c-src, with an altered Src homology 3 (SH3) domain. We will seek to identify proteins that bind differentially to the SH3 domains of the neuronal and fibroblastic forms of pp60c-src, to increase our understanding of mechanisms by which pp60c-src affects cell growth and differentiation. Finally we will study mechanisms of transactivation by p53, the association of p53 with the cellular protein, MDM2, and cell cycle control by p53, with emphasis on the possible role of phosphorylation in these processes.
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