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

Abstract

The p53 and NF-κB 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-κB. 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-κB binding site of the cyclin D1 promoter, which has been shown to bind the p52 NF-κB subunit. p53 inhibited the expression of Bcl-3 protein, a member of the IκB family that functions as a transcriptional coactivator for p52 NF-κB 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-κB function and cell cycle progression.

ACKNOWLEDGMENTS

We thank Sonia Lain and David Lane for providing many reagents and for their help and assistance. We are also grateful to Rosie Clarke for help with FACS analysis; Richard Pestell for providing the cyclin D1 reporter plasmids; Julian Blow, Michelle Garrett, and Stefan Roberts for their critical reading of the manuscript; Shreeram Sathya; Nicola Wiechens; and all the members of the N.D.P. laboratory for their help and assistance.

N.D.P. is funded by a Royal Society University Fellowship, and S.R. is funded by a grant from Cancer Research UK.