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Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm293
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Jun D cooperates with p65 to activate the proximal {kappa}B site of the cyclin D1 promoter: role of PI3Kinase/PDK-1

Kahina Toualbi-Abed1, Fanny Daniel2, Meryem C. Güller1, Agnès Legrand3, Jose-Luis Mauriz4, Alain Mauviel1 and Dominique Bernuau1

1 INSERM U697; Université Paris 7 Denis Diderot, Paris, France
2 INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, Université Paris 7 Denis Diderot, site Bichat, Paris, France
3 INSERM U591, Paris, France
4 University of Leon, Leon, Spain

Reprint requests to: D. Bernuau, Unité INSERM U 697, Pavillon Bazin, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France, Tel. 33.1.53.72.20.71 : Fax. 33.1.53.72.20.51 : E-Mail : bernuau{at}stlouis.inserm.fr

Nuclear factor kappaB (NF-{kappa}B) and Activator Protein 1 (AP-1) are transcription factors involved in the regulation of cell proliferation which play important roles in tumorigenesis. We investigated whether these two factors cooperate for transcriptional regulation of cyclin D1 (CCND1), a gene whose deregulation is critical during carcinogenesis. We demonstrate that overexpression of JunD in human hepatocarcinoma cells strongly activates transcription mediated by the {kappa}B2 site of the CCND1 promoter in reporter assays, in a manner strictly dependent on the presence of NF-{kappa}B proteins. Serum stimulation increased the expression of p65, p50, c-Fos, c-Jun and JunD, and induced the recruitment of p65, p50 and JunD to the {kappa}B2 site of the promoter in DNA pull-down assays. Chromatin immunoprecipitation (ChIP) analysis confirmed the serum-induced recruitment of JunD to the promoter in vivo and showed that the presence of JunD was dependent on the presence of p65 and p50, indicating a protein/protein-dependent mechanism of JunD recruitment. Serum-induced activation of protein binding to {kappa}B2 correlated with high levels of PDK-1 phosphorylation. Both LY294002, a specific inhibitor of PI3K, and overexpression of a dominant-negative form of PDK-1 inhibited the JunD stimulating effect in reporter assays. LY294002 also prevented the serum-induced recruitment of JunD, but not p65 or p50 to the promoter in ChIP assay. JunD/p65 complexes, identified in vivo by coimmunoprecipitation, were decreased by LY294002 and by siRNA inhibition of PDK-1. Taken together, our data demonstrate a PI3K/PDK-1-dependent functional cooperation of NF{kappa}B and JunD in the transcriptional regulation of CCND1 by serum.

Key Words: AP-1 • NFkappaB • cyclin D1 • PI3 kinase • hepatocyte

Grant support : JL Mauriz was supported by a post-doctoral grant from INSERM, France.

Received September 24, 2007; revised December 14, 2007; accepted December 15, 2007.


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