p53 represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-kappaB subunit with histone deacetylase 1.
The p53 and NF-kappaB 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-kappaB. 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-kappaB binding site of the cyclin D1 promoter, which has been shown to bind the p52 NF-kappaB subunit. p53 inhibited the expression of Bcl-3 protein, a member of the IkappaB family that functions as a transcriptional coactivator for p52 NF-kappaB 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-kappaB function and cell cycle progression.
Rocha
Sonia
S
School of Life Sciences, Division of Gene Expression and Regulation, University of Dundee, Scotland, United Kingdom.
Martin
Anthea M
AM
Meek
David W
DW
Perkins
Neil D
ND
D000081242:B-Cell Lymphoma 3 Protein; D002453:Cell Cycle; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D017930:Genes, Reporter; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008954:Models, Biological; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D012694:Serine; D012313:RNA; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases