Regulation of cellular gene expression by the viral Src oncoprotein.

Abstract

It has become increasingly evident that cells respond to extracellular stimuli through complicated signal transduction networks, which in turn regulate gene expression. Products of immediate early genes encoding transcription factors have been implicated as important mediators in converting transient signals to long-term cellular responses by regulating downstream target genes. Disruption of this tightly regulated cellular machinery, such as in oncogenesis, has profound effects on various aspects of cellular functions. To better understand the molecular mechanisms of cell transformation as well as the signaling networks involved in controlling cell proliferation, I studied regulation of immediate early gene expression by the viral Src oncoprotein. Contrary to predictions from current models of mitogenic signal transduction pathways, I discovered that serum inducibility of immediate early genes is attenuated by chronic stimulation of tyrosine kinase signaling pathways in cells stably transformed by oncogenic forms of signaling molecules, including Src. This finding suggests the existence of a negative feedback regulatory mechanism that is important in normal regulation of immediate early genes but which is perturbed in transformed cells. In a stable transfection system, my genetic analyses of the junB gene further identified a proximal promoter region involved in this transcriptional repression. To explore the possibility that other signaling mechanisms may participate in Src transformation, I extended my studies to a recently identified signaling pathway involving signal transducers and activators of transcription (STATs), which are latent cytoplasmic transcription factors. My results indicate that a Stat3-related protein is constitutively activated by Src transformation, and thus raise the possibility that Stat3 may regulate the expression of cellular genes that contribute to Src transformation. In summary, using the Src oncoprotein as a model system, I have identified a novel negative regulation of immediate early gene expression and established a direct link between STAT signaling pathways and Src transformation. These findings have not only opened new avenues for understanding the mechanisms underlying oncogenesis, but also provided further insights into the signal transduction networks involved in gene regulation.