The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.
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.
Cougot
Delphine
D
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Wu
Yuanfei
Y
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Cairo
Stefano
S
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Caramel
Julie
J
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Renard
Claire-Angélique
CA
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Lévy
Laurence
L
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Buendia
Marie Annick
MA
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France.
Neuveut
Christine
C
Unité d'Oncogene`se et Virologie Moléculaire, Institut Pasteur and INSERM U579, 28 rue du Dr. Roux, 75015 Paris, France. Electronic address: cneuveut@pasteur.fr.
D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006367:HeLa Cells; D006515:Hepatitis B virus / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication / Q000502:physiology*
D016209:Interleukin-8; D018809:Proliferating Cell Nuclear Antigen; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D017868:Cyclic AMP-Dependent Protein Kinases