Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: Role of IRF-1 and NF-kappa B

The interferon (IFN)-indueed double-stranded RNA (dsRNA)-activated Ser/Thr protein kinase (PKR) plays a role in the antiviral and antiproliferative effects of IFN, PKR phosphorylates initiation factor eIF2 alpha, thereby inhibiting protein synthesis, and also activates the transcription factor, nuclear factor-kappa B (NF-kappa B), by phosphorylating the inhibitor of NF-kappa B, I kappa B. Mice devoid of functional PKR (Pkr(o/o)) derived by targeted gene disruption exhibit a diminished response to IFN-gamma and poly(rI:rC) (pIC). In embryo fibroblasts derived from Pkr(o/o) mice, interferon regulatory factor 1 (IRF-1) or guanylate binding protein (Gbp) promoter-reporter constructs were unresponsive to IFN-gamma or pIC but response could be restored by co-transfection with PKR, The lack of responsiveness could be attributed to a diminished activation of IRF-1 and/or NF-kappa B in response to IFN-gamma or DIC. Thus, PKR acts as a signal transducer for IFN-stimulated genes dependent on the transcription Factors IRF-1 and NF-kappa B.