Hepatitis B Virus HBx Protein Activates Ras-GTP Complex Formation and Establishes a Ras, Raf, MAP Kinase Signaling Cascade

Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-10, Vol.91 (22), p.10350-10354
Main Authors: Benn, Jacqueline, Schneider, Robert J.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Binding Sites
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell Line
Cell lines
Collagenases - genetics
DNA
Genetic vectors
Guanosine Triphosphate - metabolism
Hepatitis B Antigens - metabolism
Hepatitis B virus
Hepatitis B virus - metabolism
Kinetics
Liver cells
Molecular Sequence Data
Plasmids
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-raf
ras Proteins - metabolism
Signal Transduction
Trans-Activators - metabolism
Transactivation
Transcription Factor AP-1 - metabolism
Transcription factors
Transcriptional Activation
Viruses
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Summary:Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have remained obscure. A number of studies suggest that HBx may stimulate transcription by indirectly activating transcription factors, possibly by influencing cell signaling pathways. We now present biochemical evidence that HBx activates Ras and rapidly induces a cytoplasmic signaling cascade linking Ras, Raf, and mitogen-activated protein kinase (MAP kinase), leading to transcriptional transactivation. HBx strongly elevates levels of GTP-bound Ras, activated and phosphorylated Raf, and tyrosine-phosphorylated and activated MAP kinase. Transactivation of transcription factor AP-1 by HBx is blocked by inhibition of Ras or Raf activities but not by inhibition of Ca2+- and diacylglycerol-dependent protein kinase C. HBx was also found to stimulate DNA synthesis in serum-starved cells. The hepatitis B virus HBx protein therefore stimulates Ras-GTP complex formation and promotes downstream signaling through Raf and MAP kinases, and may influence cell proliferation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.22.10350