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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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Published in: | Journal of general virology 2015-04, Vol.96 (Pt 4), p.822-832 |
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creator | Seo, Young Lan Heo, Shinhee Jang, Kyung Lib |
description | 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. |
doi_str_mv | 10.1099/vir.0.000032 |
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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.</description><identifier>ISSN: 0022-1317</identifier><identifier>EISSN: 1465-2099</identifier><identifier>DOI: 10.1099/vir.0.000032</identifier><identifier>PMID: 25535325</identifier><language>eng</language><publisher>England</publisher><subject>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</subject><ispartof>Journal of general virology, 2015-04, Vol.96 (Pt 4), p.822-832</ispartof><rights>2015 The Authors.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c395t-725d84efe20b3d5e0ce6cd11ad34e9b037db0ceb7bdf3411dbe996db100258753</citedby><cites>FETCH-LOGICAL-c395t-725d84efe20b3d5e0ce6cd11ad34e9b037db0ceb7bdf3411dbe996db100258753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25535325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seo, Young Lan</creatorcontrib><creatorcontrib>Heo, Shinhee</creatorcontrib><creatorcontrib>Jang, Kyung Lib</creatorcontrib><title>Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation</title><title>Journal of general virology</title><addtitle>J Gen Virol</addtitle><description>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.</description><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - virology</subject><subject>Cell Death - drug effects</subject><subject>Cell Death - genetics</subject><subject>Cell Line, Tumor</subject><subject>DNA Methylation</subject><subject>Down-Regulation - drug effects</subject><subject>Hep G2 Cells</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepacivirus - metabolism</subject><subject>Hepatitis C - genetics</subject><subject>Hepatitis C - metabolism</subject><subject>Hepatitis C - virology</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - virology</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - virology</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - genetics</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>Proto-Oncogene Proteins c-mdm2 - genetics</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Tumor Suppressor Protein p14ARF - biosynthesis</subject><subject>Tumor Suppressor Protein p14ARF - genetics</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Viral Core Proteins - genetics</subject><subject>Viral Core Proteins - metabolism</subject><issn>0022-1317</issn><issn>1465-2099</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNo9kD1PwzAQhi0EoqWwMSOPDKT4I46bsSofRaroAnMU25cSlMTBdgr997hq4ZaT7p57pHsRuqZkSkme329rNyVTEouzEzSmaSYSFhenaEwIYwnlVI7QhfefhNA0FfIcjZgQXHAmxigsoS9DHWqPFziqBo-1dYB7ZwPUHbZbcNq24PGSrVlSd2bQYHDZ2z5YH6_UDhv73TnYDE0UdRvc0xTDT-_A-9p2UVrih9c5biF87PaI7S7RWVU2Hq6OfYLenx7fFstktX5-WcxXiea5CIlkwsxSqIARxY0AoiHThtLS8BRyRbg0Ks6UVKbiKaVGQZ5nRtH4t5hJwSfo9uCN33wN4EPR1l5D05Qd2MEXNMtSKTM6oxG9O6DaWe8dVEXv6rZ0u4KSYp9zEcMpSHHIOeI3R_OgWjD_8F-w_BdXxXqm</recordid><startdate>201504</startdate><enddate>201504</enddate><creator>Seo, Young Lan</creator><creator>Heo, Shinhee</creator><creator>Jang, Kyung Lib</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201504</creationdate><title>Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation</title><author>Seo, Young Lan ; Heo, Shinhee ; Jang, Kyung Lib</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c395t-725d84efe20b3d5e0ce6cd11ad34e9b037db0ceb7bdf3411dbe996db100258753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - virology</topic><topic>Cell Death - drug effects</topic><topic>Cell Death - genetics</topic><topic>Cell Line, Tumor</topic><topic>DNA Methylation</topic><topic>Down-Regulation - drug effects</topic><topic>Hep G2 Cells</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - genetics</topic><topic>Hepacivirus - metabolism</topic><topic>Hepatitis C - genetics</topic><topic>Hepatitis C - metabolism</topic><topic>Hepatitis C - virology</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>Hepatocytes - virology</topic><topic>Humans</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - virology</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - genetics</topic><topic>Promoter Regions, Genetic - drug effects</topic><topic>Proto-Oncogene Proteins c-mdm2 - genetics</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Tumor Suppressor Protein p14ARF - biosynthesis</topic><topic>Tumor Suppressor Protein p14ARF - genetics</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Viral Core Proteins - genetics</topic><topic>Viral Core Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seo, Young Lan</creatorcontrib><creatorcontrib>Heo, Shinhee</creatorcontrib><creatorcontrib>Jang, Kyung Lib</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of general virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seo, Young Lan</au><au>Heo, Shinhee</au><au>Jang, Kyung Lib</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation</atitle><jtitle>Journal of general virology</jtitle><addtitle>J Gen Virol</addtitle><date>2015-04</date><risdate>2015</risdate><volume>96</volume><issue>Pt 4</issue><spage>822</spage><epage>832</epage><pages>822-832</pages><issn>0022-1317</issn><eissn>1465-2099</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><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.</abstract><cop>England</cop><pmid>25535325</pmid><doi>10.1099/vir.0.000032</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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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 |
title | Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation |
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