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Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-κB subunit p65

Oncogene volume 26, pages 7457–7466 (2007)Cite this article

Abstract

Both genotoxic and oncogenic stress activates the nuclear factor-kappa B (NF-κB) and p53 proteins; however, the p53 activity is antagonized by NF-κB signaling. Dmp1 is a Myb-like transcription factor that activates the Arf-p53 pathway. The Dmp1 promoter was activated by a classical NF-κB activator tumor necrosis factor α, but repressed by treatment of cells with non-classical NF-κB activators, anthracyclins and UV-C. p65 and other subsets of NF-κB proteins were bound to the Dmp1 promoter following anthracyclin/UV-C treatment of rodent fibroblasts. This resulted in the downregulation of Dmp1 mRNA and protein. Repression of the Dmp1 transcription by anthracyclins depended on the unique NF-κB site on the promoter. Downregulation of p65 significantly attenuated the repression of the Dmp1 promoter by anthracyclins/UV-C. The amount of Dmp1 bound to the Arf promoter decreased significantly upon anthracyclin treatment; this, in turn, downregulated the Arf levels. Repression of the Arf promoter by p65 or anthracyclins depended on Dmp1, which was significantly attenuated in Dmp1−/− cells. Both Dmp1−/−and Arf−/−cells showed resistance to anthracyclin-induced cell death compared to wild-type cells; non-immortalized p65-knockdown cells were much more sensitive. Thus, the Dmp1-Arf pathway is repressed by p65 in response to genotoxic stress, which implicates a novel mechanism of p53 inactivation by NF-κB.

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Acknowledgements

We thank Dr George Kulik and Ms Karen Klein for critical reading of the manuscript and Drs Neil Perkins, Alexander Hoffmann, Bruce Torbett and Mario Tschan for helpful discussions and sharing unpublished data. We are grateful to Drs Gioacchino Natoli, Andrew Thorburn, Michael Ostrowski, Charles Sherr and Martine Roussel for plasmid DNAs. We also thank Ramesh Sreeramaneni and Scott Barton for technical assistance. This work was supported by NIH/NCI 5R01CA106314 (K Inoue) and by a Wake Forest University Comprehensive Cancer Center ‘Push’ grant (Center grant CA12197-31) to K Inoue.

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  1. The Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA

    P Taneja, A Mallakin, L A Matise, D P Frazier, M Choudhary & K Inoue

  2. The Department of Cancer Biology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA

    P Taneja, A Mallakin, L A Matise, D P Frazier, M Choudhary & K Inoue

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  1. P Taneja
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Correspondence to K Inoue.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Taneja, P., Mallakin, A., Matise, L. et al. Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-κB subunit p65. Oncogene 26, 7457–7466 (2007). https://doi.org/10.1038/sj.onc.1210568

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