Requirement of the cyclic adenosine monophosphate response element-binding protein for hepatitis B virus replication

Bo Kyung Kim, Seoung Ok Lim, Yun Gyu Park

Research output: Contribution to journalArticle

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Abstract

The cyclic adenosine monophosphate-response element (CRE)-transcription factor complex participates in the regulation of viral gene expression and pathologic processes caused by various viruses. The hepatitis B virus (HBV) enhancer I directs liver-specific transcription of viral genes and contains a CRE sequence (HBV-CRE); however, whether the HBV-CRE and CRE-binding protein (CREB) are required for the HBV life cycle remains to be determined. This study was designed to investigate the role of CREB in HBV replication and gene expression. Sequence-comparison analysis of 984 HBVs reported worldwide showed that the HBV-CRE sequence is highly conserved, indicating the possibility that it plays an important role in the HBV life cycle. The binding of CREB to the HBV-CRE site was markedly inhibited by oligonudeotides containing HBV-CRE and consensus CRE sequences in vitro and in vivo. The HBV promoter activity was demonstrated to be dependent upon the transactivation activity of CREB. Treatment with CRE decoy oligonucleotides reduced HBV promoter activity, and this was reversed by CREB overexpression. The levels of viral transcripts, DNA, and antigens were remarkably decreased in response to the overexpression of CREB mutants or treatment with the CRE decoy oligonudeotides, whereas enhancing CREB activity increased the levels of viral transcripts. In addition, introduction of a three-base mutation into the HBV-CRE led to a marked reduction in HBV messenger RNA synthesis. Conclusion: Taken together, our results demonstrate that both replication and gene expression of HBV require a functional CREB and HBV-CRE. We have also demonstrated that CRE decoy oligonucleotides and the overexpression of CREB mutants can effectively block the HBV life cycle, suggesting that interventions against CREB activity could provide a new avenue to treat HBV infection.

Original languageEnglish
Pages (from-to)361-373
Number of pages13
JournalHepatology
Volume48
Issue number2
DOIs
Publication statusPublished - 2008 Aug 1

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Response Elements
Virus Replication
Hepatitis B virus
Cyclic AMP
Carrier Proteins
Life Cycle Stages
IgA receptor
Oligonucleotides
Viral Gene Expression Regulation
Gene Expression
Viral Genes
Viral Antigens
Viral DNA
Consensus Sequence
Virus Diseases
Pathologic Processes
Transcriptional Activation

ASJC Scopus subject areas

  • Hepatology

Cite this

Requirement of the cyclic adenosine monophosphate response element-binding protein for hepatitis B virus replication. / Kim, Bo Kyung; Lim, Seoung Ok; Park, Yun Gyu.

In: Hepatology, Vol. 48, No. 2, 01.08.2008, p. 361-373.

Research output: Contribution to journalArticle

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