Abstract
NF-κB/rel proteins, tumor suppressor p53, and oncogene c-Myc are critical transcription factors involved in coordinating cellular decision-making events in response to external stimuli. Consensus sequences for binding these three transcription factors are found in the promoter region of IEX-1 (Immediate Early response gene X-1) gene that can either suppress or induce apoptosis in a cell- and stimulus-dependent manner. Utilizing an electrophoretic mobility shift assay (EMSA) and a promoter/reporter assay, we show that the NF-κB/rel consensus sequence in the IEX-1 promoter is specifically bound and activated by multiple NF-κB/rel complexes in descending order p65-c-rel→p65–50→p50–50. Interestingly, NF-κB/rel-mediated activation of IEX-1 expression was synergized by p53, but strongly inhibited by c-Myc in a dose-dependent fashion. Moreover, the ability of c-Myc to inhibit IEX-1 expression requires the presence of functional p53, which may partially contribute to the varying effects of p53 on IEX-1 expression in different cells. In support of coordinated regulation of IEX-1 expression by these three transcription factors in vivo, binding of endogenous p53, c-Myc and NF-κB/rel proteins, including p50, p65 and c-rel, to the IEX-1 promoter was demonstrated in living cells by chromatin immunoprecipitation using specific antibodies. The study reveals a novel integrative regulation of specific gene expression by NF-κB/rel, p53 and c-Myc transcription factors.
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Acknowledgements
We thank Drs D Baltimore, A Hoffman and M Scott for p65KO3T3 cells (RelA−/− MEF) and plasmid pGD-RelA, Tse-Hua Tan for p50 and c-rel constructs, and X-H Feng for a c-Myc construct. We are grateful to Dr Peggy J Farnham for sharing his ChIP protocol and to Drs Milton Finegold, Robert A Edwards and Li-Yuan Yu-Lee for critical reading of this manuscript. This work was supported by National Institutes of Health grant AI45003, Research Scholar Grant RSG-01-178-01-MGO from the American Cancer Society, and a Moran foundation award (PRJ 00-109) from Baylor College Medicine (to MX Wu).
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Huang, YH., Wu, J., Zhang, Y. et al. Synergistic and opposing regulation of the stress-responsive gene IEX-1 by p53, c-Myc, and multiple NF-κB/rel complexes. Oncogene 21, 6819–6828 (2002). https://doi.org/10.1038/sj.onc.1205854
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DOI: https://doi.org/10.1038/sj.onc.1205854
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