title: Mechanism for transcriptional synergy between interferon regulatory factor (IRF)-3 and IRF-7 in activation of the interferon-beta gene promoter.
abstract: The interferon-beta promoter has been studied extensively as a model system for combinatorial transcriptional regulation. In virus-infected cells the transcription factors ATF-2, c-Jun, interferon regulatory factor (IRF)-3, IRF-7 and NF-kappaB, and the coactivators p300/CBP play critical roles in the activation of this and other promoters. It remains unclear, however, why most other combinations of AP-1, IRF and Rel proteins fail to activate the interferon-beta gene. Here we have explored how different IRFs may cooperate with other factors to activate transcription. First we showed in undifferentiated embryonic carcinoma cells that ectopic expression of either IRF-3 or IRF-7, but not IRF-1, was sufficient to allow virus-dependent activation of the interferon-beta promoter. Moreover, the activity of IRF-3 and IRF-7 was strongly affected by promoter context, with IRF-7 preferentially being recruited to the natural interferon-beta promoter. We fully reconstituted activation of this promoter in insect cells. Maximal synergy required IRF-3 and IRF-7 but not IRF-1, and was strongly dependent on the presence of p300/CBP, even when these coactivators only modestly affected the activity of each factor by itself. These results suggest that specificity in activation of the interferon-beta gene depends on a unique promoter context and on the role played by coactivators as architectural factors.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0576, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.forename: Gang
authors.initials: G
authors.lastname: Ma
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lin
authors.forename: Melissa
authors.initials: M
authors.lastname: Orr
authors.forename: Marc G
authors.initials: MG
authors.lastname: Wathelet
mesh_terms: D000818:Animals; D002374:Catalase / Q000032:analysis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007313:Insecta / Q000166:cytology; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018243:Teratocarcinoma / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014775:Virus Activation; D001616:beta-Galactosidase / Q000032:analysis
chemical_list: D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016899:Interferon-beta; D002374:Catalase; D001616:beta-Galactosidase; D005978:Glutathione