Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2

• Published in: Oncogene Vol. 18; no. 12; pp. 2129 - 2137
• Main Authors: COCCIA, E. M, DEL RUSSO, N, STELLACCI, E, ORSATTI, R, BENEDETTI, E, MARZIALI, G, HISCOTT, J, BATTISTINI, A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 25.03.1999; Nature Publishing Group
• Subjects: 2',5'-Oligoadenylate Synthetase - genetics; Binding sites; Biological and medical sciences; Cell Cycle - genetics; Cell cycle, cell proliferation; Cell growth; Cell physiology; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - genetics; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Ectopic expression; Enzyme Activation; Enzyme Repression; Fundamental and applied biological sciences. Psychology; Gene regulation; Genes; Immune response; Interferon; Interferon Regulatory Factor-1; Interferon Regulatory Factor-2; Interferon-gamma - pharmacology; Kinases; Models, Genetic; Molecular and cellular biology; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - genetics; Phosphoproteins - metabolism; Promoter Regions, Genetic; Promoters; Protein Binding; Recombinant Proteins - metabolism; Repressor Proteins; Transcription; Transcription Factors - metabolism; Transcriptional Activation; Cell proliferation; Vertebrata; Regulation(control); Mammalia; Cell line; Gene; Mouse; Transcription promoter; Rodentia; Activation; Repression; Gene expression
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202536

The Interferon Regulatory Factors-1 and -2 (IRF-1 and IRF-2) were originally identified as transcriptional regulators of the interferon (IFN) and IFN-stimulated genes. These factors also modulate immune response and play a role in cell growth regulation. In this study we analysed the effect of the ectopic expression of IRF-1 and IRF-2 on the regulation of two potential IRF target genes involved in cell growth regulation, 2-5A synthetase and p21 (WAF/CP1), both of which contain consensus binding sites for IRF family members within their promoters. Following ectopic expression, IRF-1 transactivated 2-5A synthetase and p21 genes, an effect that was counterbalanced by concomitant ectopic expression of IRF-2. These effects were mediated by direct binding of IRF to the gene promoters. A construct expressing an IRF-2 antisense (FRI-2) was able to revert the inhibitory effect of IRF-2 on the IRF-1 transactivation. IRF-1 also induced expression of its homologous repressor IRF-2 as indicated by EMSA analysis using an IRF-E probe from the IRF-2 promoter; and by cotransfection of IRF-1 together with an IRF-2 promoter CAT construct. Therefore, the induction of IRF-1 by IFNs or other stimuli acts as a transactivator of genes involved in cell growth regulation, as well as of its own repressor IRF-2, thus providing autoinhibitory regulation of IRF-1 activated genes.