Identification and characterization of interferon and double-stranded RNA signal transduction pathways

grantor: University of TorontoIFNs are cytokines that mediate antiviral and antiproliferative effects in many cells. A potent inducer of IFN is the double-stranded RNA (dsRNA) motifs found in many viruses. Since the double-stranded RNA (dsRNA)-activated IFN-induced protein kinase (PKR) is activated by binding dsRNA, we reasoned that PKR may be acting as a signal-transducer, transducing the signal from dsRNA to transcription factors through a phosphorylation event. These activated transcription factors translocate to the nucleus and induce transcription of their cognate genes which mediate IFNs antiviral and antiproliferative effects. We show that in response to dsRNA, PKR activates transcription factors NF-$\kappa$B and IRF-1. DSRNA-dependent activation of NF-$\kappa$B and IRF-1 is ablated in PKR-deleted mouse embryo fibroblasts and in Hela cells that have been depleted of PKR using anti-sense PKR oligonucleotide. PKR has been previously implicated in dsRNA dependent translational regulation through the phosphorylation of translation factor eukariotic initiation factor 2 (eIF2). Here we expand the role of PKR as a regulator of transcription.Ph.D