Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice.
In human chronic hepatitis C, alcohol intake is a synergistic factor for the acceleration of hepatocarcinogenesis. Recently, we showed a significant increase of reactive oxygen species (ROS) in hepatitis C virus (HCV) core-transgenic mice fed ethanol-containing diets. Because previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase (GST), which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to the pathogenesis of liver disease of HCV-infected patients with high ethanol consumption.
D051698:Activating Transcription Factor 2; D000818:Animals; D018797:Cell Cycle Proteins / Q000032:analysis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D016174:Hepacivirus / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000032:analysis; D014758:Viral Core Proteins / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D016328:NF-kappa B; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014758:Viral Core Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000431:Ethanol; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases