Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation

Infection with hepatitis C virus (HCV) is characterized by systemic oxidative stress that is caused by either viral core protein or chronic inflammation. It is well recognized that reactive oxygen species (ROS) such as H2O2 can induce apoptotic cell death and can therefore function as anti-tumorigen...

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Bibliographic Details
Published in:Journal of general virology 2015-04, Vol.96 (Pt 4), p.822-832
Main Authors: Seo, Young Lan, Heo, Shinhee, Jang, Kyung Lib
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Apoptosis - genetics
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - virology
Cell Death - drug effects
Cell Death - genetics
Cell Line, Tumor
DNA Methylation
Down-Regulation - drug effects
Hep G2 Cells
Hepacivirus - drug effects
Hepacivirus - genetics
Hepacivirus - metabolism
Hepatitis C - genetics
Hepatitis C - metabolism
Hepatitis C - virology
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatocytes - virology
Humans
Hydrogen Peroxide - pharmacology
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - virology
Oxidative Stress - drug effects
Oxidative Stress - genetics
Promoter Regions, Genetic - drug effects
Proto-Oncogene Proteins c-mdm2 - genetics
Proto-Oncogene Proteins c-mdm2 - metabolism
Reactive Oxygen Species - metabolism
Tumor Suppressor Protein p14ARF - biosynthesis
Tumor Suppressor Protein p14ARF - genetics
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Viral Core Proteins - genetics
Viral Core Proteins - metabolism
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Summary:Infection with hepatitis C virus (HCV) is characterized by systemic oxidative stress that is caused by either viral core protein or chronic inflammation. It is well recognized that reactive oxygen species (ROS) such as H2O2 can induce apoptotic cell death and can therefore function as anti-tumorigenic species. However, the detailed mechanisms by which ROS induce apoptotic cell death and HCV copes with the oxidative conditions are largely unknown. In the present study, we found that H2O2 induced apoptotic cell death in p53-positive human hepatocytes, but not in p53-negative human hepatocytes. For this effect, H2O2 upregulated levels of p14, increased ubiquitin-dependent degradation of mouse double minute 2 (MDM2), and reduced the interaction between MDM2 and p53 to prevent p53 degradation, resulting in accumulation of p53 and subsequent activation of p53-dependent apoptotic pathways. Interestingly, HCV core repressed p14 expression via promoter hypermethylation to abolish the potential of H2O2 to activate the p14-MDM2-p53 pathway. As a consequence, HCV core-expressing cells could overcome p53-mediated apoptosis provoked by H2O2. Taken together, HCV core could contribute to hepatocellular carcinoma formation by removing deleterious roles of ROS inducing cell death.
ISSN:0022-1317
1465-2099
DOI:10.1099/vir.0.000032