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Molecular and Cellular Biology, July 2003, p. 4713-4727, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4713-4727.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

p53 Represses Cyclin D1 Transcription through Down Regulation of Bcl-3 and Inducing Increased Association of the p52 NF-{kappa}B Subunit with Histone Deacetylase 1

Sonia Rocha,1 Anthea M. Martin,2 David W. Meek,2 and Neil D. Perkins1*

School of Life Sciences, Division of Gene Expression and Regulation, University of Dundee,1 Biomedical Research Centre, Ninewells Hospital, Dundee, Scotland, United Kingdom2

Received 24 February 2003/ Accepted 10 April 2003

The p53 and NF-{kappa}B transcription factor families are important, multifunctional regulators of the cellular response to stress. Here we have investigated the regulatory mechanisms controlling p53-dependent cell cycle arrest and cross talk with NF-{kappa}B. Upon induction of p53 in H1299 or U-2 OS cells, we observed specific repression of cyclin D1 promoter activity, correlating with a decrease in cyclin D1 protein and mRNA levels. This repression was dependent on the proximal NF-{kappa}B binding site of the cyclin D1 promoter, which has been shown to bind the p52 NF-{kappa}B subunit. p53 inhibited the expression of Bcl-3 protein, a member of the I{kappa}B family that functions as a transcriptional coactivator for p52 NF-{kappa}B and also reduced p52/Bcl-3 complex levels. Concomitant with this, p53 induced a significant increase in the association of p52 and histone deacetylase 1 (HDAC1). Importantly, p53-mediated suppression of the cyclin D1 promoter was reversed by coexpression of Bcl-3 and inhibition of p52 or deacetylase activity. p53 therefore induces a transcriptional switch in which p52/Bcl-3 activator complexes are replaced by p52/HDAC1 repressor complexes, resulting in active repression of cyclin D1 transcription. These results reveal a unique mechanism by which p53 regulates NF-{kappa}B function and cell cycle progression.

* Corresponding author. Mailing address: School of Life Sciences, Division of Gene Expression and Regulation, MSI/WTB Complex, Dow St., University of Dundee, Dundee, DD1 5EH Scotland, United Kingdom. Phone: 44 1382 345 606. Fax: 44 1382 348 072. E-mail: n.d.perkins{at}dundee.ac.uk.

Molecular and Cellular Biology, July 2003, p. 4713-4727, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4713-4727.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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