Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B.
The induction of interferon (IFN) genes by viruses or double-stranded RNA (dsRNA) requires the assembly of a complex set of transcription factors on responsive DNA elements of IFN gene promoters. One of the factors necessary for regulating IFN-beta gene transcription is nuclear factor NF-kappa B, the activation of which is triggered by dsRNA. It has previously been suggested that the dsRNA-activated p68 protein kinase (PKR) may act as an inducer-receptor, transducing the signal from dsRNA to NF-kappa B through phosphorylation of the inhibitor I kappa B. We present direct evidence that PKR can phosphorylate I kappa B-alpha (MAD-3) and activate NF-kappa B DNA binding activity in vitro. We further show that dsRNA induces an unusual phosphorylated form of I kappa B-alpha. The expression of a transdominant mutant PKR is able to perturb the dsRNA-mediated signaling pathway in vivo, suggesting a role for this kinase in IFN-beta gene induction.
Kumar
A
A
Department of Cancer Biology, Cleveland Clinic Foundation, OH 44195.
Haque
J
J
Lacoste
J
J
Hiscott
J
J
Williams
B R
BR
D000818:Animals; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008264:Macrophages; D051379:Mice; D008970:Molecular Weight; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014162:Transfection; D019892:eIF-2 Kinase
D016328:NF-kappa B; D010710:Phosphates; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C497594:Relb protein, mouse; D014157:Transcription Factors; D051841:Transcription Factor RelB; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase