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J. Biol. Chem., Vol. 282, Issue 7, 4277-4287, February 16, 2007

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The Hepatitis B Virus X Protein Functionally Interacts with CREB-binding Protein/p300 in the Regulation of CREB-mediated Transcription^*

From the Unité d’Oncogenèse et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France

The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of liver cancer. The virus encodes a multifunctional regulator, the hepatitis B virus X protein (HBx), that is essential for virus replication. HBx is involved in modulating signal transduction pathways and transcription mediated by various factors, notably CREB that requires the recruitment of the co-activators CREB-binding protein (CBP)/p300. Here we investigated the role of HBx and its potential interaction with CBP/p300 in regulating CREB transcriptional activity. We show that HBx and CBP/p300 synergistically enhanced CREB activity and that CREB phosphorylation by protein kinase A was a prerequisite for the cooperative action of HBx and CBP/p300. We further show that HBx interacted directly with CBP/p300 in vitro and in vivo. Using chromatin immunoprecipitation, we provide evidence that HBx physically occupied the CREB-binding domain of CREB-responsive promoters of endogenous cellular genes such as interleukin 8 and proliferating cell nuclear antigen. Moreover expression of HBx increased the recruitment of p300 to the interleukin 8 and proliferating cell nuclear antigen promoters in cells, and this is associated with increased gene expression. As recruitment of CBP/p300 is known to represent the limiting event for activating CREB target genes, HBx may disrupt this cellular regulation, thus predisposing cells to transformation.

Received for publication, July 17, 2006 , and in revised form, December 5, 2006.

^* This work was supported in part by Association pour la Recherche sur le Cancer (ARC) Grant 3379. 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.

¹ Supported by a fellowship from the Ministère de la recherche et des Technologies.

² Supported by an ARC fellowship. Present address: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St., Worcester, MA 01605.

³ Supported by GIS-Institut des Maladies Rares.

⁴ Present address: INSERM U509, Laboratoire de Pathologie Moléculaire des Cancers, Inst. Curie, 26 rue d’Ulm, 75005 Paris, France.

⁵ Supported by an ARC fellowship. Present address: Laboratory of Developmental Signalling, Cancer Research UK London Research Inst., 44 Lincoln’s Inn Fields, London WC2A 3PX, UK.

⁶ To whom correspondence should be addressed: Unité d’Oncogenèse et Virologie Moléculaire (INSERM U579), Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France. Tel.: 33-145-68-88-51; Fax: 33-145-68-89-43; E-mail: cneuveut{at}pasteur.fr.

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