This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tarn, C. Articles by Andrisani, O. M. Search for Related Content PubMed PubMed Citation Articles by Tarn, C. Articles by Andrisani, O. M.

Hepatitis B Virus X Protein Activates the p38 Mitogen-Activated Protein Kinase Pathway in Dedifferentiated Hepatocytes

Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana

Received 18 March 2002/ Accepted 15 June 2002

Hepatitis B virus X protein (pX) is implicated in hepatocarcinogenesis by an unknown mechanism. Employing a cellular model linked to pX-mediated transformation, we investigated the role of the previously reported Stat3 activation by pX in hepatocyte transformation. Our model is composed of a differentiated hepatocyte (AML12) 3pX-1 cell line that undergoes pX-dependent transformation and a dedifferentiated hepatocyte (AML12) 4pX-1 cell line that does not exhibit transformation by pX. We report that pX-dependent Stat3 activation occurs only in non-pX-transforming 4pX-1 cells and conclude that Stat3 activation is not linked to pX-mediated transformation. Maximum Stat3 transactivation requires Ser727 phosphorylation, mediated by mitogenic pathway activation. Employing dominant negative mutants and inhibitors of mitogenic pathways, we demonstrate that maximum, pX-dependent Stat3 transactivation is inhibited by the p38 mitogen-activated protein kinase (MAPK)-specific inhibitor SB 203580. Using transient-transreporter and in vitro kinase assays, we demonstrate for the first time that pX activates the p38 MAPK pathway only in 4pX-1 cells. pX-mediated Stat3 and p38 MAPK activation is Ca²⁺ and c-Src dependent, in agreement with the established cellular action of pX. Importantly, pX-dependent activation of p38 MAPK inactivates Cdc25C by phosphorylation of Ser216, thus initiating activation of the G₂/M checkpoint, resulting in 4pX-1 cell growth retardation. Interestingly, pX expression in the less differentiated hepatocyte 4pX-1 cells activates signaling pathways known to be active in regenerating hepatocytes. These results suggest that pX expression in the infected liver effects distinct mitogenic pathway activation in less differentiated versus differentiated hepatocytes.

This article has been cited by other articles:

• Clippinger, A. J., Bouchard, M. J. (2008). Hepatitis B Virus HBx Protein Localizes to Mitochondria in Primary Rat Hepatocytes and Modulates Mitochondrial Membrane Potential. J. Virol. 82: 6798-6811 [Abstract] [Full Text]  
• Kim, S., Kim, H.-Y., Lee, S., Kim, S. W., Sohn, S., Kim, K., Cho, H. (2007). Hepatitis B Virus X Protein Induces Perinuclear Mitochondrial Clustering in Microtubule- and Dynein-Dependent Manners. J. Virol. 81: 1714-1726 [Abstract] [Full Text]  
• Li, H., Chi, C.-Y., Lee, S., Andrisani, O. M. (2006). The Mitogenic Function of Hepatitis B Virus X Protein Resides within Amino Acids 51 to 140 and Is Modulated by N- and C-Terminal Regulatory Regions. J. Virol. 80: 10554-10564 [Abstract] [Full Text]  
• Hargett, D., McLean, T., Bachenheimer, S. L. (2005). Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38. J. Virol. 79: 8348-8360 [Abstract] [Full Text]  
• Bouchard, M. J., Schneider, R. J. (2004). The Enigmatic X Gene of Hepatitis B Virus. J. Virol. 78: 12725-12734 [Full Text]  
• Wang, W.-H., Gregori, G., Hullinger, R. L., Andrisani, O. M. (2004). Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-{alpha} Expression. Mol. Cell. Biol. 24: 10352-10365 [Abstract] [Full Text]  
• Yun, C., Cho, H., Kim, S.-J., Lee, J.-H., Park, S. Y., Chan, G. K., Cho, H. (2004). Mitotic Aberration Coupled With Centrosome Amplification Is Induced by Hepatitis B Virus X Oncoprotein via the Ras-Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Pathway. Mol Cancer Res 2: 159-169 [Abstract] [Full Text]