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J. Biol. Chem., Vol. 282, Issue 29, 20854-20867, July 20, 2007

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Transcriptional Regulation of the Bovine Leukemia Virus Promoter by the Cyclic AMP-response Element Modulator Isoform^*

Thi Lien-Anh Nguyên¹², Stéphane de Walque²³, Emmanuelle Veithen, Ann Dekoninck⁴, Valérie Martinelli⁵, Yvan de Launoit, Arsène Burny, Robert Harrod^¶, and Carine Van Lint⁴⁶

From the Institut de Biologie et de Médecine Moléculaires, Laboratoire de Virologie Moléculaire, Université Libre de Bruxelles, Rue des Profs Jeener et Brachet 12, 6041 Gosselies, Belgium, the Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille 1, UMR 8117 CNRS, BP 447, 1 Rue Calmette, 59021 Lille Cedex, France, and the ^¶Department of Biological Sciences, Laboratory of Molecular Virology, Southern Methodist University, Dallas, Texas 75275-0376

Bovine leukemia virus (BLV) expression is controlled at the transcriptional level through three Tax_BLV-responsive elements (TxREs) responsive to the viral transactivator Tax_BLV. The cAMP-responsive element (CRE)-binding protein (CREB) has been shown to interact with CRE-like sequences present in the middle of each of these TxREs and to play critical transcriptional roles in both basal and Tax_BLV-transactivated BLV promoter activity. In this study, we have investigated the potential involvement of the cAMP-response element modulator (CREM) in BLV transcriptional regulation, and we have demonstrated that CREM proteins were expressed in BLV-infected cells and bound to the three BLV TxREs in vitro. Chromatin immunoprecipitation assays using BLV-infected cell lines demonstrated in the context of chromatin that CREM proteins were recruited to the BLV promoter TxRE region in vivo. Functional studies, in the absence of Tax_BLV, indicated that ectopic CREM protein had a CRE-dependent stimulatory effect on BLV promoter transcriptional activity. Cross-link of the B-cell receptor potentiated CREM transactivation of the viral promoter. Further experiments supported the notion that this potentiation involved CREM Ser-117 phosphorylation and recruitment of CBP/p300 to the BLV promoter. Although CREB and Tax_BLV synergistically transactivated the BLV promoter, CREM repressed this Tax_BLV/CREB synergism, suggesting that a modulation of the level of Tax_BLV transactivation through opposite actions of CREB and CREM could facilitate immune escape and allow tumor development.

Received for publication, April 11, 2007 , and in revised form, May 23, 2007.

^* This work was supported in part by grants (to C. V. L.) from the "Fonds National de la Recherche Scientifique" (Belgium), the Télévie Program of the Fonds National de la Recherche Scientifique, the "Action de Recherche Concertée du Ministère de la Communauté Franaise," ULB, ARC Program 04/09-309, the Internationale Brachet Stiftung, the Interreg III Program ("Intergenes" Project), the Theyskens-Mineur Foundation, the "Fortis Banque Assurance," and the "Fédération Belge Contre le Cancer." 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. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) EF507802.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Fellow of the Belgian Fonds pour la Recherche dans l'Industrie et l'Agriculture (FRIA) and of the FNRS Télévie Program. Present address: Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, 3755 Cote Ste. Catherine, Montreal, Quebec H3T 1E2, Canada.

² Both authors contributed equally to this work.

³ Supported by a postdoctoral fellowship from the Région Wallonne Program Waleo2 616295.

⁴ Chargé de Recherches of the Fonds National de la Recherche Scientifique.

⁵ Fellow of the Fonds National de la Recherche Scientifique Télévie Program.

⁶ Directeur de Recherches of the Fonds National de la Recherche Scientifique. To whom correspondence should be addressed: Université Libre de Bruxelles, Institut de Biologie et de Médecine Moléculaires, Laboratoire de Virologie Moléculaire, Rue des Profs Jeener et Brachet 12, 6041 Gosselies, Belgium. Tel.: 32-2-650-9807; Fax: 32-2-650-9800; E-mail: cvlint{at}ulb.ac.be.

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