Delphine Cougot | PubMed Health

PubMed2006

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.

CREB-Binding Protein↗

PubMed2005

HBV induced carcinogenesis.

Hepatocellular carcinoma (HCC) is one of the rare human neoplasms associated with viral infections. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important etiological factors of HCC, accounting for more than 70% of cases worldwide. The risk of HCC development is greatly increased in chronic viral carriers exposed to other recognized risk factors, including exposure to aflatoxin B1, alcoholic cirrhosis and diabetes. The importance of HBV genotypes and precore or core promoter mutants remains incompletely understood. The role of HBV in tumour formation appears to be complex and may involve both direct and indirect mechanisms. Integration of HBV DNA into the host genome occurs at early steps of clonal tumour expansion, and it has been shown to induce direct insertional mutagenesis of diverse cancer-related genes in a number of cases. Chronic liver inflammation and hepatic regeneration induced by cellular immune responses may favour the accumulation of genetic alterations in infected hepatocytes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein LHBs may contribute in deregulating the cellular transcription program and proliferation control, and sensitize liver cells to carcinogenic factors. Recent genetic studies have provided insight into the mechanisms underlying viral-associated hepatocarcinogenesis. It has been shown that the rate of chromosomal alterations is significantly increased in HBV-related tumours compared with tumours associated with other risk factors. HBV might therefore play a role in enhancing genomic instability. Inactivation of p53 by mutations and regional allelic deletions is found more frequently in tumours associated with HBV infection. By contrast, HBV related tumours harbour a low rate of beta-catenin mutations. Together, these data strongly support the notion that chronic HBV infection might trigger specific oncogenic pathways, thus playing a role beyond stimulation of host immune responses and chronic necro-inflammatory liver disease.

Animals↗