Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-kappaB.
The interferon (IFN)-induced 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 eIF2alpha, thereby inhibiting protein synthesis, and also activates the transcription factor, nuclear factor-kappaB (NF-kappaB), by phosphorylating the inhibitor of NF-kappaB, IkappaB. 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-kappaB in response to IFN-gamma or pIC. Thus, PKR acts as a signal transducer for IFN-stimulated genes dependent on the transcription factors IRF-1 and NF-kappaB.
Kumar
A
A
Department of Cancer Biology, The Cleveland Clinic Foundation, OH 44195, USA.
Yang
Y L
YL
Flati
V
V
Der
S
S
Kadereit
S
S
Deb
A
A
Haque
J
J
Reis
L
L
Weissmann
C
C
Williams
B R
BR
D000818:Animals; D015152:Blotting, Northern; D016207:Cytokines / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012330:RNA, Double-Stranded / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D019892:eIF-2 Kinase
D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D012330:RNA, Double-Stranded; D014157:Transcription Factors; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase