RNA-dependent protein kinase PKR is required for activation of NF-kappa B by IFN-gamma in a STAT1-independent pathway.
The IFN-inducible dsRNA-activated protein kinase PKR regulates protein synthesis through phosphorylation of eukaryotic initiation factor-2alpha. It also acts as a signal transducer for transcription factors NF-kappaB, IFN regulatory factor-1, and activating transcription factor-2. IFN-gamma, a pleiotropic cytokine, elicits gene expression by activating the Janus kinase-STAT signaling pathway. IFN-gamma can synergize with TNF-alpha to activate NF-kappaB in a number of cell lines. Here we show that IFN-gamma alone can activate NF-kappaB, by a Janus kinase-1-mediated, but Stat1-independent, mechanism. NF-kappaB activation by IFN-gamma is associated with degradation of IkappaB beta. The IFN-gamma response can be blocked by 2',5'-oligoadenylate-linked antisense chimeras against PKR mRNA. There was no activation of NF-kappaB by IFN in PKR-null cells, indicating that PKR is required for IFN-gamma signaling to NF-kappaB.
Deb
A
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Department of Cancer Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Haque
S J
SJ
Mogensen
T
T
Silverman
R H
RH
Williams
B R
BR
D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D019892:eIF-2 Kinase