MECHANISM OF GROWTH FACTOR-INDUCED TRANSFORMATION

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Analysis of the mechanisms of cellular transformation by transduction of specific genes (by retroviral infection, by transfection of tumor cell DNA or by over-expression of normal cellular genes) indicate that a common feature is the alteration in the function or regulation of specific components in signal transduction pathways that mediate the response of cells to mitogenic stimulation. The long-term objectives of this application are to determine the molecular mechanisms involved in transformation induced by altered regulation of growth factor- mediated signal transduction pathways. A central factor in the mitogenic response involves the activation of protein kinase C (PKC), a calcium and phospholipid-dependent kinase that has been demonstrated to be activated in pathways of both proliferation and differentiation. Therefore, alterations in the regulation of PKC activity may have a dramatic effect on growth control. In fact, the over-expression of PKC activity and a PKC-regulated gene, termed phorbin, in fibroblasts has been demonstrated to induce a transformed phenotype. The preliminary evidence suggests that the mechanism of transformation by phorbin is mediated through an autocrine process. This application outlines an experimental approach to determine if alterations in PKC or phorbin gene expression can be identified in specific types of human tumors or transformed lines, to determine the role of the phorbin protein in transformation, to identify the critical regions of the protein that are required for the induction of transformation, and to determine the role of this protein in PKC-mediated effects on cell differentiation. Answering these questions will yield critical information about the function of PKC-mediated signal transduction pathways in cell growth and differentiation and about the role of altered regulation of these pathways in cellular transformation. Mechanistic studies of signal transduction will have applications in cancer diagnosis, in the design therapeutic strategies, and also in identification of the molecular mechanisms of growth control which that play a role in other disease processes.