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.
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 cell 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-Fos 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-fos 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.
Benn
J
J
Department of Biochemistry and Kaplan Cancer Center, New York University Medical Center, New York 10016, USA.
Su
F
F
Doria
M
M
Schneider
R J
RJ
D000818:Animals; D002460:Cell Line; D006509:Hepatitis B / Q000378:metabolism / Q000821:virology*; D006515:Hepatitis B virus / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D054334:Viral Regulatory and Accessory Proteins
D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D011494:Protein Kinases