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

Oncogene volume 18, pages 2129–2137 (1999)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr MW Taylor for critical reading of the manuscript, Dr B Vogelstein for the generous gift of the p21 constructs and Dr T Taniguchi for the IRF2-CAT construct; Sabrina Tocchio for secretarial and editorial assistance; Eugenio Morassi and Roberto Gilardi for preparing drawings. This work was supported by grants from the Consiglio Nazionale delle Ricerche, Progetto Finalizzato ACRO 96.00743.39 and Italy-USA Program on `Therapy of Tumors' to A Battistini and from the Medical Research Council of Canada to J Hiscott. Emilia Stellacci was supported by a postdoctoral fellowship from AIRC.

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Authors and Affiliations

  1. Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome, 00161, Italy

    Eliana M Coccia, Nicoletta Del Russo, Emilia Stellacci, Roberto Orsatti, Eleonora Benedetti, Giovanna Marziali & Angela Battistini

  2. Laboratory of Immunology, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome, 00161, Italy

    Eliana M Coccia

  3. Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, H3T 1E2, Quebec, Canada

    John Hiscott

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  1. Eliana M Coccia
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Coccia, E., Russo, N., Stellacci, E. et al. Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2. Oncogene 18, 2129–2137 (1999). https://doi.org/10.1038/sj.onc.1202536

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