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 antiprolif erative effects of IFN, PKR phosphorylates initiation factor eIF2 alph a, thereby inhibiting protein synthesis, and also activates the transc ription factor, nuclear factor-kappa B (NF-kappa B), by phosphorylatin g the inhibitor of NF-kappa B, I kappa B. Mice devoid of functional PK R (Pkr(o/o)) derived by targeted gene disruption exhibit a diminished response to IFN-gamma and poly(rI:rC) (pIC). In embryo fibroblasts der ived from Pkr(o/o) mice, interferon regulatory factor 1 (IRF-1) or gua nylate binding protein (Gbp) promoter-reporter constructs were unrespo nsive to IFN-gamma or pIC but response could be restored by co-transfe ction with PKR, The lack of responsiveness could be attributed to a di minished activation of IRF-1 and/or NF-kappa B in response to IFN-gamm a or DIC. Thus, PKR acts as a signal transducer for IFN-stimulated gen es dependent on the transcription Factors IRF-1 and NF-kappa B.