Signal transduction mechanisms mediating interferon-alpha induction of gene expressio

The transmission of extracellular signals across the plasma membrane is an essential process in the regulated growth and development of mammalian cells and tissues. Signal transduction is initiated by receptors in the plasma membrane which each specifically bind one, or a few of an array of distinct differentiating agents, hormones, and growth factors (Chapter 1). The definition of specific intracellular signals which mediate cellular responses to a given factor is a central problem in molecular biology. Progress has been made in identifying signal transduction pathways activated by growth factor receptors, however the biochemical pathways mediating growth inhibitory responses are undefined. The interferons (IFNs) are potent polypeptide growth inhibitors which appear to antagonize growth factors in the physiological regulation of cell growth. The interaction of IFNs with their membrane receptors rapidly activates the transcription of a defined group of genes, the products of which are required in the biological response to IFN. I have found that the extent of the transcriptional response to IFN$alpha$ depends on the degree of IFN$alpha$ receptor occupancy at the cell surface, implying that membrane events are critical for the transcriptional activation of these IFN-inducible genes (Chapter 2). The transcriptional response to IFN$alpha$ is mediated by an enhancer sequence which has been named the IFN-stimulated response element (ISRE). The ISRE is activated in vitro and in vivo by IFN$alpha$ and platelet-derived growth factor (PDGF), indicating some degree of overlap in the early signal transduction pathways triggered by these antagonistic growth regulators. Activation of the ISRE by IFN and PDGF (Chapter 3) however, does not seem to occur via the same biochemical pathway, as these inductions are differentially sensitive to inhibitors of protein kinase activity (Chapter 4). IFN$alpha$ appears to signal the ISRE through activation of a phospholipase A$sb2$ activity, resulting in the release of arachidonic acid and activation of ISRE-binding factors. These data suggest a novel signalling role for eicosanoid second messengers in the cytoplasmic activation of specific transcription factors (Chapter 5).