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Molecular and Cellular Biology, September 2003, p. 6200-6209, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6200-6209.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Potentiation of Tumor Necrosis Factor-Induced NF-{kappa}B Activation by Deacetylase Inhibitors Is Associated with a Delayed Cytoplasmic Reappearance of I{kappa}B{alpha}

Emmanuelle Adam,1 Vincent Quivy,1 Françoise Bex,2 Alain Chariot,3 Yves Collette,4 Caroline Vanhulle,1 Sonia Schoonbroodt,3 Véronique Goffin,1 Thi Liên-Anh Nguyên,1 Geoffrey Gloire,3 Géraldine Carrard,5 Bertrand Friguet,5 Yvan de Launoit,6,7 Arsène Burny,1 Vincent Bours,3 Jacques Piette,3 and Carine Van Lint1*

Institut de Biologie et de Médecine Moléculaires, Service de Chimie Biologique, Laboratoire de Virologie Moléculaire, Université Libre de Bruxelles, 6041 Gosselies,1 Laboratoire de Microbiologie, CERIA, and,2 Faculté de Médecine, Laboratoire de Virologie Moléculaire, Université Libre de Bruxelles, 1070 Brussels,6 Center for Molecular and Cellular Therapy, Sart-Tilman, Université de Liège, 4000 Liège, Belgium,3 INSERM U119, 13009 Marseille,4 Laboratoire de Biologie et Biochimie Cellulaire du Vieillissement, Université Paris 7—Denis Diderot, 75251 Paris Cedex 05,5 Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille 1, UMR 8117 CNRS, 59021 Lille Cedex, France7

Received 4 December 2002/ Returned for modification 22 January 2003/ Accepted 31 May 2003

Previous studies have implicated acetylases and deacetylases in regulating the transcriptional activity of NF-{kappa}B. Here, we show that inhibitors of deacetylases such as trichostatin A (TSA) and sodium butyrate (NaBut) potentiated TNF-induced expression of several natural NF-{kappa}B-driven promoters. This transcriptional synergism observed between TNF and TSA (or NaBut) required intact {kappa}B sites in all promoters tested and was biologically relevant as demonstrated by RNase protection on two instances of endogenous NF-{kappa}B-regulated gene transcription. Importantly, TSA prolonged both TNF-induced DNA-binding activity and the presence of NF-{kappa}B in the nucleus. We showed that the p65 subunit of NF-{kappa}B was acetylated in vivo. However, this acetylation was weak, suggesting that other mechanisms could be implicated in the potentiated binding and transactivation activities of NF-{kappa}B after TNF plus TSA versus TNF treatment. Western blot and immunofluorescence confocal microscopy experiments revealed a delay in the cytoplasmic reappearance of the I{kappa}B{alpha} inhibitor that correlated temporally with the prolonged intranuclear binding and presence of NF-{kappa}B. This delay was due neither to a defect in I{kappa}B{alpha} mRNA production nor to a nuclear retention of I{kappa}B{alpha} but was rather due to a persistent proteasome-mediated degradation of I{kappa}B{alpha}. A prolongation of I{kappa}B kinase activity could explain, at least partially, the delayed I{kappa}B{alpha} cytoplasmic reappearance observed in presence of TNF plus TSA.

* Corresponding author. Mailing address: Université Libre de Bruxelles, Institut de Biologie et de Médecine Moléculaires, Service de Chimie Biologique, Laboratoire de Virologie Moléculaire, Rue des Profs Jeener et Brachet, 12, 6041 Gosselies, Belgium. Phone: 32-2-650-9807. Fax: 32-2-650-9800. E-mail: cvlint{at}ulb.ac.be.

Molecular and Cellular Biology, September 2003, p. 6200-6209, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6200-6209.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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