Identification and characterization of an interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-independent signaling pathway for IFN-alpha.
Transcriptional activation of genes containing the interferon (IFN)-stimulated response element (ISRE) by IFN-alpha is known to be mediated through the post-translational activation of IFN-stimulated gene factor 3 (ISGF3) and its subsequent interactions with the ISRE. We have identified an ISRE-ISGF3-independent signaling pathway used by IFN-alpha for the induction of the IFN regulatory factor 1 (IRF-1) gene. A minimal functional promoter of the IRF-1 gene does not contain an ISRE, but we have shown that transcription of the IRF-1 gene is activated by IFN-alpha in cell lines that do not produce ISGF3 activity due to the absence of functional ISGF3-gamma (p48) polypeptide. This ISRE-ISGF3-independent pathway for IFN-alpha signaling involves a cis-acting enhancer element located in the IRF-1 promoter, termed the inverted repeat (IR) element, and its cognate trans-acting factor, IR-binding factor alpha (IRBF-alpha). IFN-gamma also activates a transcription factor(s) that forms a different complex (IRBF-gamma) with the IR element. Protein-tyrosine kinase (tyk2) activity is required for the induction of IRBF-alpha, but not IRBF-gamma. The p91 subunit of ISGF3 is necessary for the formation of both IRBF-alpha and IRBF-gamma.
Department of Cancer Biology, Cleveland Clinic Foundation, Ohio 44195.
S J
SJ
Haque
B R
BR
Williams
D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases