title: Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation.
abstract: 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.
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea.
authors.forename: Young Lan
authors.initials: YL
authors.lastname: Seo
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea.
authors.forename: Shinhee
authors.initials: S
authors.lastname: Heo
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea.
authors.forename: Kyung Lib
authors.initials: KL
authors.lastname: Jang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D006861:Hydrogen Peroxide; D051736:Proto-Oncogene Proteins c-mdm2