Activation of multiple growth regulatory genes following inducible expression of IRF-1 or IRF/RelA fusion proteins (original) (raw)
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- Published: 18 September 1997
Oncogene volume 15, pages 1425–1435 (1997)Cite this article
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Abstract
Interferon Regulatory Factor (IRF)-1 has been characterized as an important growth regulatory and immunomodulatory transcription factor. To further characterize the potential targets of IRF-1 antiproliferative activity, IRF-1 was expressed under the control of the tetracycline-inducible system in murine NIH3T3 cells. Due to their ability to mimic IRF-1 transactivator function, the regulatory potential of IRF-1/RelA and IRF-2/RelA fusion proteins consisting of the DNA binding domains of IRF-1 or IRF-2 fused to the transactivation domain of NF-κB RelA(p65) was also examined. Cells inducibly expressing IRF-1 or IRF/RelA in response to doxycycline treatment displayed significantly reduced growth rates compared to control cells, and inhibition of cell growth correlated directly with the level of transgene expression. Interestingly, IRF-1 and IRF/RelA expression also induced a low level of apoptosis, as detected by microscopic analyses. Furthermore, expression of the interferon inducible, double stranded RNA dependent kinase PKR was increased following IRF-1 or IRF/RelA induction. Most strikingly, induction of IRF-1 and IRF/RelA expression resulted in a significant increase in STAT1 (p91) protein and increased ISGF3 DNA binding activity, suggesting that IRF-1 tumor suppressor activity may involve a novel mechanism which activates the JAK-STAT pathway through STAT1. WAF1 levels were also constitutively elevated in IRF-1 and IRF-1/RelA cells. These studies demonstrate that inducible expression of the transactivation function of IRF-1 or IRF/RelA mediates tumor suppressor activity by inducing cell growth arrest, apoptosis and the differential activation of growth regulatory genes such as PKR, STAT1 and WAF1.
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Authors and Affiliations
- Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, H3T 1E2, Quebec, Canada
Hannah Nguyen, Rongtuan Lin & John Hiscott - Department of Microbiology and Immunology, McGill University, Montreal, H3T 1E2, Quebec, Canada
Hannah Nguyen & John Hiscott - Department of Medicine, McGill University, Montreal, H3T 1E2, Quebec, Canada
Rongtuan Lin & John Hiscott
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- Hannah Nguyen
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Nguyen, H., Lin, R. & Hiscott, J. Activation of multiple growth regulatory genes following inducible expression of IRF-1 or IRF/RelA fusion proteins.Oncogene 15, 1425–1435 (1997). https://doi.org/10.1038/sj.onc.1201318
- Received: 21 February 1997
- Revised: 29 May 1997
- Accepted: 29 May 1997
- Issue Date: 18 September 1997
- DOI: https://doi.org/10.1038/sj.onc.1201318