Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen- activated protein kinases

Jacqueline Benn, Fei Su, Margherita Doria, Robert J. Schneider

Research output: Contribution to journalArticlepeer-review

Abstract

The HBx protein of hepatitis B virus is a dual-specificity activator of transcription, stimulating signal transduction pathways in the cytoplasm and transcription factors in the nucleus, when expressed in celt lines in culture. In the cytoplasm, HBx was shown to stimulate the Ras-Raf-mitogen- activated protein kinase (MAP kinase) cascade, which is essential for activation of transcription factor AP-1. Here we show that HBx protein stimulates two independently regulated members of the MAP kinase family when expressed transiently in cells. HBx protein stimulates the extracellular signal-regulated kinases (ERKs) and the c-Jun N-terminal kinases (JNKs). HBx activation of ERKs and JNKs leads to induction and activation of AP-1 DNA binding activity involving transient de novo synthesis of c-Fox protein and prolonged synthesis of c-Jun, mediated by N-terminal phosphorylation of c- Jun carried out by HBx-activated JNK. New c-Jun synthesis was blocked by coexpression with a dominant-negative MAP kinase kinase (MEK kinase, MEKK- 1), confirming that HBx stimulates the prolonged synthesis of c-Jun by activating JNK signalling pathways. Activation of the c-fox gene was blocked by coexpression with a Raf-C4 catalytic mutant, confirming that HBx induces c-Fos by acting on Ras-Raf linked pathways. HBx activation of ERK and JNK pathways resulted in prolonged accumulation of AP-1-c-Jun dimer complexes. HBx activation of JNK and sustained activation of c-Jun, should they occur in the context of hepatitis B virus infection, might play a role in viral transformation and pathogenesis.

Original languageEnglish
Pages (from-to)4978-4985
Number of pages8
JournalJournal of Virology
Volume70
Issue number8
Publication statusPublished - Aug 1996

ASJC Scopus subject areas

  • Immunology

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