NFkappaB activation is required for interferon regulatory factor-1-mediated interferon beta induction.
The interferon regulatory factor 1 (IRF-1) acts as a transcriptional inducer of the interferon beta (IFN-beta) gene and interferon-stimulated genes. Here we report that IRF-1-mediated IFN-beta induction depends on NFkappaB activity. IRF-1 by itself initiates NFkappaB activation by inducing a reduction in cellular MAD3/IkappaBalpha, an inhibitor of NFkappaB. After nuclear translocation, NFkappaB synergizes with IRF-1 on the cis-elements positive regulatory domain (PRD)II and PRDI/III to induce transcription of the IFN-beta gene. In contrast with IFN-beta transcription induced by dsRNA or virus, c-Jun/ATF-2 binding to PRDIV is not involved. Recombinant MAD3/IkappaBalpha is phosphorylated in vitro by extracts from IRF-1-expressing cells. IRF-1-dependent MAD3/IkappaBalpha degradation is not detectable in cells expressing a dominant negative mutant of the protein kinase PKR, suggesting that PKR mediates MAD3/IkappaBalpha degradation.
Kirchhoff
S
S
Department of Gene Regulation and Differentiation, National Research Center for Biotechnology, Braunschweig, Germany.
Wilhelm
D
D
Angel
P
P
Hauser
H
H
D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D020672:I-kappa B Proteins; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000235:genetics*; D008856:Microscopy, Fluorescence; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014162:Transfection; D019892:eIF-2 Kinase / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; D000072000:NF-KappaB Inhibitor alpha; D016899:Interferon-beta; D019892:eIF-2 Kinase