The oncoprotein encoded in Rous sarcoma virus, v-Src, is an activated tyrosine kinase for which the mechanism of oncogenesis remains elusive. Activation of the normal cellular homolog of the viral oncoprotein, c- Src, is associated with significant human cancers, including carcinomas of the breast and colon. Our long-term goal is to understand the molecular basis of how activated Src kinase subverts signal transduction pathways involved in cell growth control and thereby induces oncogenesis. Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors that were originally identified as key signaling molecules in mediating responses to cytokine stimulation. Recently, we made the novel observation that the Src tyrosine kinase constitutively activates one STAT family member, Stat3, thus linking STAT signaling pathways with Src oncogenesis. This finding opens new avenues for investigating the role of STATs in oncogenesis, which will be explored further in the proposed experiments. To assess how well activation of STAT signaling pathways correlates with cell transformation, Specific Aim 1 will investigate the activation of different STATs by various Src mutants and diverse oncoproteins. Because STATs are transcription factors that translocate to the nucleus, Specific Aim 2 will examine transcriptional regulation by STATs in response to Src and other oncoproteins. For this purpose, we will investigate regulation of recombinant and endogenous genes containing DNA response elements for STATs in transformed cells. To more critically evaluate the role of STATs in cell transformation, Specific Aim 3 will test the biological consequences of expressing dominant-negative and constitutively-activated forms of STATs, especially Stat3, in transfected cells. Results of these experiments will provide direct evidence on whether Stat3 has a causal role in cell transformation. Finally, Specific Aim 4 will screen human tumor cells in which c-Src is implicated, particularly breast and colon cancers, for activation of STATs. Taken together, results of our experiments will provide new information on the extent to which STAT signaling pathways participate in Src oncogenesis and human cancer. New insights gained from these studies may point to novel strategies for effective therapies against human cancers that involve the Src kinase.
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