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J. Biol. Chem., Vol. 279, Issue 33, 35025-35036, August 13, 2004

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Deacetylase Inhibitors and the Viral Transactivator Tax_BLV Synergistically Activate Bovine Leukemia Virus Gene Expression via a cAMP-responsive Element- and cAMP-responsive Element-binding Protein-dependent Mechanism^*

Thi Liên-Anh Nguyên, Claire Calomme¶, Gaëlle Wijmeersch, Séverine Nizet||, Emmanuelle Veithen, Daniel Portetelle**, Yvan de Launoit¶¶, Arsène Burny, and Carine Van Lint, Maître de Recherches of the Fonds National de la Recherche Scientifique||||

From the 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, ^**Faculté Universitaire des Sciences Agronomiques de Gembloux, Département de Biologie Moléculaire, 5030 Gembloux, Belgium, Université Libre de Bruxelles, Faculté de Médecine, Laboratoire de Virologie Moléculaire, 808 Route de Lennik, 1070 Bruxelles, Belgium, and ^¶¶Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille 1, Unité Mixte Recherche 8117 Centre National de la Recherche Scientifique, BP 447, 1 Rue Calmette, 59021 Lille Cedex, France

Efficient bovine leukemia virus (BLV) transcription requires the virus-encoded transactivator Tax_BLV, which acts through three Tax_BLV-responsive elements located in the 5' long terminal repeat. It has been proposed that the binding of the CRE-binding protein (CREB) and the activating transcription factor (ATF) to the three imperfect cAMP-responsive elements (CREs) located in each Tax_BLV-responsive element mediates Tax_BLV transactivation. Here we demonstrated that deacetylase inhibitors (HDACis) synergistically enhanced the transcriptional activation of the BLV promoter by Tax_BLV in a CRE-dependent manner. Tax_BLV was acetylated in vivo at its N terminus but not at internal lysine residues. Rather, HDACi potentiation of Tax_BLV transactivation was mediated by an HDACi indirect action that requires new protein synthesis. Mechanistically, using a dominant-negative form of CREB, we showed that Tax_BLV and HDACi synergistically activated BLV gene expression via a CREB-dependent mechanism. Moreover, electrophoretic mobility shift assay and Western blot experiments revealed that HDACi increased the in vitro DNA binding activity of CREB/ATF but did not alter CREB/ATF intranuclear presence. Remarkably, chromatin immunoprecipitation assays demonstrated that HDACi treatment increased the level of CREB bound to the BLV promoter in vivo. Our results together suggest that an increase in CREB/ATF occupancy of the viral CREs in response to HDACi potentiates Tax_BLV transactivation of the BLV promoter.

Received for publication, April 13, 2004

^* This work was supported by grants from the Fonds National de la Recherche Scientifique (Belgium) (to C. V. L.), the Télévie Program, the Action de Recherche concertée du Ministère de la Communauté française (Université Libre de Bruxelles, ARC program no. 98/03-224), the Internationale Brachet Stiftung, the Fortis Banque Assurance, the Fédération Belge contre le Cancer, and the Theyskens-Mineur Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Fellows of the Fonds National de la Recherche Scientifique-Télévie Program.

^¶ Chargé de Recherches of the Fonds National de la Recherche Scientifique.

^|| Present address: GlaxoSmithKline, Research and Development, DAP Viral Service, Rue de L'Institut 89, 1330 Rixensart, Belgium.

^|||| To whom correspondence should be addressed. Tel.: 32-2-650 9807; Fax: 32-2-650 9800; E-mail: cvlint{at}ulb.ac.be.

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