RRC ID 39631
Author Saito H, Morita Y, Fujimoto M, Narazaki M, Naka T, Kishimoto T.
Title IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-gamma.
Journal J Immunol
Abstract STAT-induced STAT inhibitor-1 (SSI-1), also referred to as suppressor of cytokine signaling-1 and JAK-binding protein, is a member of a new family, the members of which are negative regulators of cytokine signals. SSI-1 is induced by various cytokines; however, the transcriptional mechanism of the SSI-1 gene is not fully understood. Here, we showed that transcription of the mouse SSI-1 gene was initiated from six adjoining sites accompanying three GC boxes and a single GC box-like element near them, but not from the TATA box or an initiator sequence. We also showed that IFN-gamma induced SSI-1 mRNA more strongly than IL-6 in NIH-3T3 fibroblasts and that this IFN-gamma effect was mediated by Stat1. To determine the signal pathway downstream of Stat1, transcriptional activities of several mutant promoters were examined. The region mediating stimulatory effect of IFN-gamma to the gene transcription was localized to the -88/-60 region containing three tandem GAAA units, named variant IFN-gamma-responsive element (VIRE), while four IFN-gamma activation site (GAS)-like elements located far upstream were not related to the IFN-gamma response. Gel-shift assays revealed that IFN-gamma induced IFN regulatory factor-1 (IRF-1) binding to VIRE, but not that of IRF-2 or three components of ISGF3. Furthermore, forced expression of IRF-1 mimicked and that of IRF-2 inhibited the stimulatory effect of IFN-gamma on SSI-1 gene transcription. Finally, mouse embryonal fibroblasts lacking IRF-1 showed impaired SSI-1 mRNA induction by IFN-gamma. These results demonstrated that IRF-1, which is induced by activation of Stat1, mediated transcriptional activation of the SSI-1 gene by IFN-gamma via VIRE.
Volume 164(11)
Pages 5833-43
Published 2000-6-1
DOI 10.4049/jimmunol.164.11.5833
PII ji_v164n10p5833
PMID 10820262
MeSH 3T3 Cells / metabolism Animals Base Sequence Carrier Proteins / biosynthesis Carrier Proteins / chemistry Carrier Proteins / genetics* Carrier Proteins / metabolism Cytokines / pharmacology DNA-Binding Proteins / deficiency DNA-Binding Proteins / genetics DNA-Binding Proteins / physiology* Drug Synergism Electrophoresis, Polyacrylamide Gel Fibroblasts / metabolism Growth Substances / pharmacology Interferon Regulatory Factor-1 Interferon-gamma / physiology* Mice Molecular Sequence Data Phosphoproteins / deficiency Phosphoproteins / genetics Phosphoproteins / physiology* Promoter Regions, Genetic / immunology* RNA, Messenger / biosynthesis Repressor Proteins* Response Elements / immunology Signal Transduction / genetics Signal Transduction / immunology* Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins Tandem Repeat Sequences / immunology Trans-Activators / physiology* Transcription, Genetic / immunology Tumor Necrosis Factor-alpha / physiology
IF 4.886
Times Cited 78
Human and Animal Cells MC3T3-E1(RCB1126)