Abstract
An upstream inverted repeat (IR) element mediates transcriptional activation of the interferon response factor-1 gene (IRF-1) by interferon (IFN)-alpha and IFN-gamma. IFN-alpha and IFN-gamma fail to induce IRF-1 in cells that lack signal transducer and activator of transcription 1 (STAT1), and STAT1 homodimers bind to IR elements in extracts of IFN-alpha-treated cells. We now report that STAT2 also plays an important role in the IFN-alpha-mediated transcriptional activation of the IRF-1 gene. A new factor, most likely a STAT1-STAT2 heterodimer, was detected with an IR probe in extracts of IFN-alpha-treated cells. STAT1 and STAT2 are already known to combine with p48, a DNA-binding protein, to form IFN-stimulated gene factor 3 (ISGF3), which binds to IFN-stimulated response elements (ISREs) distinct from the IR of the IRF-1 gene. In extracts of U2A cells, which lack p48, STAT1-STAT2 heterodimers were still formed, indicating that they do not contain p48. We manipulated the intracellular levels of STAT1-STAT2 heterodimers and STAT1 homodimers to examine their roles in the induction of IRF-1 by IFN-alpha. Although both dimers can induce IRF-1 transcription, the heterodimers are more potent and thus may be the major activators in vivo. Deletion analysis reveals that the C-terminal domain of STAT2 is important for transcriptional activation mediated by both STAT1-STAT2 heterodimers and ISGF3.
Highlights
Many cytokine and growth factor signaling pathways utilize proteins of the JAK1 and STAT families [1,2,3]
We propose that transcriptional activation of the interferon response factor-1 gene (IRF-1) gene involves interaction of the inverted repeat (IR) element with either a signal transducer and activator of transcription 1 (STAT1)-STAT2 heterodimer or a STAT1 homodimer
We did not identify a GAS element specific for heterodimers since STAT1 homodimers were detected with the same probes
Summary
Many cytokine and growth factor signaling pathways utilize proteins of the JAK1 and STAT families [1,2,3]. Activated STAT1 and STAT2 associate with the DNA-binding protein p48 to form the transcription factor ISGF3, which recognizes an interferon-. 1 Abbreviations used are: JAK, Janus family kinases, including TYK2 and JAK1; EMSA, electrophoretic mobility shift assay; Fc␥, high affinity immunoglobulin G chain receptor gene; GAF, ␥-activated factor; GAS, ␥-activated sequence; IFN, interferon; IR, inverted repeat; IRF-1, interferon response factor-1; ISGF3, interferon-stimulated gene factor 3; ISRE, interferon-stimulated response element; p48, 48-kDa DNA binding component of ISGF3; SH2, Src-homology domain 2; STAT, signal transducer and activator of transcription; WAF-1, wild-type p53activated factor 1. We demonstrate the formation of a novel IFN-␣-inducible DNA-binding factor consisting of STAT1 and STAT2 This factor does not include p48, the level of p48 protein does affect the balance between the novel factor and ISGF3. We propose that transcriptional activation of the IRF-1 gene involves interaction of the IR element with either a STAT1-STAT2 heterodimer or a STAT1 homodimer
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