Genus Beta Human Papillomavirus E6 Proteins Vary in Their Effects on the Transactivation of p53 Target Genes
Identifieur interne : 000097 ( Pmc/Corpus ); précédent : 000096; suivant : 000098Genus Beta Human Papillomavirus E6 Proteins Vary in Their Effects on the Transactivation of p53 Target Genes
Auteurs : Elizabeth A. White ; Johanna Walther ; Hassan Javanbakht ; Peter M. HowleySource :
- Journal of Virology [ 0022-538X ] ; 2014.
Abstract
The genus beta human papillomaviruses (beta HPVs) cause cutaneous lesions and are thought to be involved in the initiation of some nonmelanoma skin cancers (NMSCs), particularly in patients with the genetic disorder epidermodysplasia verruciformis (EV). We have previously reported that at least two of the genus beta HPV E6 proteins bind to and/or increase the steady-state levels of p53 in squamous epithelial cells. This is in contrast to a well-characterized ability of the E6 proteins of cancer-associated HPVs of genus alpha HPV, which inactivate p53 by targeting its ubiquitin-mediated proteolysis. In this study, we have investigated the ability of genus beta E6 proteins from eight different HPV types to block the transactivation of p53 target genes following DNA damage. We find that the E6 proteins from diverse beta HPV species and types vary in their capacity to block the induction of MDM2, p21, and proapoptotic genes after genotoxic stress. We conclude that some genus beta HPV E6 proteins inhibit at least some p53 target genes, although perhaps not by the same mechanism or to the same degree as the high-risk genus alpha HPV E6 proteins.
Url:
DOI: 10.1128/JVI.01197-14
PubMed: 24850740
PubMed Central: 4135955
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Hoffmann-La Roche Ltd., Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Howley, Peter M" sort="Howley, Peter M" uniqKey="Howley P" first="Peter M." last="Howley">Peter M. Howley</name><affiliation><nlm:aff id="aff1">Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24850740</idno><idno type="pmc">4135955</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135955</idno><idno type="RBID">PMC:4135955</idno><idno type="doi">10.1128/JVI.01197-14</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000097</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000097</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genus Beta Human Papillomavirus E6 Proteins Vary in Their Effects on the Transactivation of p53 Target Genes</title><author><name sortKey="White, Elizabeth A" sort="White, Elizabeth A" uniqKey="White E" first="Elizabeth A." last="White">Elizabeth A. White</name><affiliation><nlm:aff id="aff1">Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Walther, Johanna" sort="Walther, Johanna" uniqKey="Walther J" first="Johanna" last="Walther">Johanna Walther</name><affiliation><nlm:aff id="aff2">Infectious Diseases, F. Hoffmann-La Roche Ltd., Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Javanbakht, Hassan" sort="Javanbakht, Hassan" uniqKey="Javanbakht H" first="Hassan" last="Javanbakht">Hassan Javanbakht</name><affiliation><nlm:aff id="aff2">Infectious Diseases, F. Hoffmann-La Roche Ltd., Basel, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Howley, Peter M" sort="Howley, Peter M" uniqKey="Howley P" first="Peter M." last="Howley">Peter M. Howley</name><affiliation><nlm:aff id="aff1">Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>The genus beta human papillomaviruses (beta HPVs) cause cutaneous lesions and are thought to be involved in the initiation of some nonmelanoma skin cancers (NMSCs), particularly in patients with the genetic disorder epidermodysplasia verruciformis (EV). We have previously reported that at least two of the genus beta HPV E6 proteins bind to and/or increase the steady-state levels of p53 in squamous epithelial cells. This is in contrast to a well-characterized ability of the E6 proteins of cancer-associated HPVs of genus alpha HPV, which inactivate p53 by targeting its ubiquitin-mediated proteolysis. In this study, we have investigated the ability of genus beta E6 proteins from eight different HPV types to block the transactivation of p53 target genes following DNA damage. We find that the E6 proteins from diverse beta HPV species and types vary in their capacity to block the induction of MDM2, p21, and proapoptotic genes after genotoxic stress. We conclude that some genus beta HPV E6 proteins inhibit at least some p53 target genes, although perhaps not by the same mechanism or to the same degree as the high-risk genus alpha HPV E6 proteins.</p><p><bold>IMPORTANCE</bold> This study addresses the ability of various human papillomavirus E6 proteins to block the activation of p53-responsive cellular genes following DNA damage in human keratinocytes, the normal host cell for HPVs. The E6 proteins encoded by the high-risk, cancer-associated HPV types of genus alpha HPV have a well-established activity to target p53 degradation and thereby inhibit the response to DNA damage. In this study, we have investigated the ability of genus beta HPV E6 proteins from eight different HPV types to block the ability of p53 to transactivate downstream genes following DNA damage. We find that some, but not all, genus beta HPV E6 proteins can block the transactivation of some p53 target genes. This differential response to DNA damage furthers the understanding of cutaneous HPV biology and may help to explain the potential connection between some beta HPVs and cancer.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Virol</journal-id><journal-id journal-id-type="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24850740</article-id><article-id pub-id-type="pmc">4135955</article-id><article-id pub-id-type="publisher-id">01197-14</article-id><article-id pub-id-type="doi">10.1128/JVI.01197-14</article-id><article-categories><subj-group subj-group-type="heading"><subject>Virus-Cell Interactions</subject></subj-group></article-categories><title-group><article-title>Genus Beta Human Papillomavirus E6 Proteins Vary in Their Effects on the Transactivation of p53 Target Genes</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>White</surname><given-names>Elizabeth A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Walther</surname><given-names>Johanna</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Javanbakht</surname><given-names>Hassan</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Howley</surname><given-names>Peter M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><label>a</label>Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA</aff><aff id="aff2"><label>b</label>Infectious Diseases, F. Hoffmann-La Roche Ltd., Basel, Switzerland</aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Imperiale</surname><given-names>M. J.</given-names></name><role>Editor</role></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Peter M. Howley, <email>peter_howley@hms.harvard.edu</email>.</corresp></author-notes><pub-date pub-type="ppub"><month>8</month><year>2014</year></pub-date><volume>88</volume><issue>15</issue><fpage>8201</fpage><lpage>8212</lpage><history><date date-type="received"><day>26</day><month>4</month><year>2014</year></date><date date-type="accepted"><day>14</day><month>5</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2014, American Society for Microbiology. All Rights Reserved.</copyright-statement><copyright-year>2014</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zjv01514008201.pdf"></self-uri><abstract><title>ABSTRACT</title><p>The genus beta human papillomaviruses (beta HPVs) cause cutaneous lesions and are thought to be involved in the initiation of some nonmelanoma skin cancers (NMSCs), particularly in patients with the genetic disorder epidermodysplasia verruciformis (EV). We have previously reported that at least two of the genus beta HPV E6 proteins bind to and/or increase the steady-state levels of p53 in squamous epithelial cells. This is in contrast to a well-characterized ability of the E6 proteins of cancer-associated HPVs of genus alpha HPV, which inactivate p53 by targeting its ubiquitin-mediated proteolysis. In this study, we have investigated the ability of genus beta E6 proteins from eight different HPV types to block the transactivation of p53 target genes following DNA damage. We find that the E6 proteins from diverse beta HPV species and types vary in their capacity to block the induction of MDM2, p21, and proapoptotic genes after genotoxic stress. We conclude that some genus beta HPV E6 proteins inhibit at least some p53 target genes, although perhaps not by the same mechanism or to the same degree as the high-risk genus alpha HPV E6 proteins.</p><p><bold>IMPORTANCE</bold> This study addresses the ability of various human papillomavirus E6 proteins to block the activation of p53-responsive cellular genes following DNA damage in human keratinocytes, the normal host cell for HPVs. The E6 proteins encoded by the high-risk, cancer-associated HPV types of genus alpha HPV have a well-established activity to target p53 degradation and thereby inhibit the response to DNA damage. In this study, we have investigated the ability of genus beta HPV E6 proteins from eight different HPV types to block the ability of p53 to transactivate downstream genes following DNA damage. We find that some, but not all, genus beta HPV E6 proteins can block the transactivation of some p53 target genes. This differential response to DNA damage furthers the understanding of cutaneous HPV biology and may help to explain the potential connection between some beta HPVs and cancer.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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