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dc.contributor.authorShamanin, Vladimir A.
dc.contributor.authorSekaric, Pedja
dc.contributor.authorAndrophy, Elliot J.
dc.date2022-08-11T08:09:38.000
dc.date.accessioned2022-08-23T16:38:19Z
dc.date.available2022-08-23T16:38:19Z
dc.date.issued2008-02-08
dc.date.submitted2009-11-13
dc.identifier.citationJ Virol. 2008 Apr;82(8):3912-20. Epub 2008 Feb 6. <a href="http://dx.doi.org/10.1128/JVI.02466-07">Link to article on publisher's site</a>
dc.identifier.issn1098-5514 (Electronic)
dc.identifier.doi10.1128/JVI.02466-07
dc.identifier.pmid18256148
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39222
dc.description.abstractTwo activities of human papillomavirus type 16 E6 (HPV16 E6) are proposed to contribute to the efficient immortalization of human epithelial cells: the degradation of p53 protein and the induction of telomerase. However, the requirement for p53 inactivation has been debated. Another E6 target is the hAda3 protein, a p53 coactivator and a component of histone acetyltransferase complexes. We have previously described the role of hAda3 and p53 acetylation in p14ARF-induced human mammary epithelial cell (MEC) senescence (P. Sekaric, V. A. Shamanin, J. Luo, and E. J. Androphy, Oncogene 26:6261-6268, 2007). In this study, we analyzed a set of HPV16 E6 mutants for the ability to induce hAda3 degradation. E6 mutants that degrade hAda3 but not p53 could abrogate p14ARF-induced growth arrest despite the presence of normal levels of p53 and efficiently immortalized MECs. However, two E6 mutants that previously were reported to immortalize MECs with low efficiency were found to be defective for both p53 and hAda3 degradation. We found that these immortal MECs select for reduced p53 protein levels through a proteasome-dependent mechanism. The findings strongly imply that the inactivation of the p14ARF-p53 pathway, either by the E6-mediated degradation of p53 or hAda3 or by cellular adaptation, is required for MEC immortalization.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18256148&dopt=Abstract">Link to Article in PubMed</a>
dc.subjectCell Aging
dc.subjectCell Line
dc.subject*Cell Transformation, Viral
dc.subjectEpithelial Cells
dc.subjectHuman papillomavirus 16
dc.subjectHumans
dc.subjectOncogene Proteins, Viral
dc.subjectRepressor Proteins
dc.subjectTranscription Factors
dc.subjectTumor Suppressor Protein p14ARF
dc.subjectTumor Suppressor Protein p53
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titlehAda3 degradation by papillomavirus type 16 E6 correlates with abrogation of the p14ARF-p53 pathway and efficient immortalization of human mammary epithelial cells
dc.typeJournal Article
dc.source.journaltitleJournal of virology
dc.source.volume82
dc.source.issue8
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3027&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2028
dc.identifier.contextkey1063411
refterms.dateFOA2022-08-23T16:38:20Z
html.description.abstract<p>Two activities of human papillomavirus type 16 E6 (HPV16 E6) are proposed to contribute to the efficient immortalization of human epithelial cells: the degradation of p53 protein and the induction of telomerase. However, the requirement for p53 inactivation has been debated. Another E6 target is the hAda3 protein, a p53 coactivator and a component of histone acetyltransferase complexes. We have previously described the role of hAda3 and p53 acetylation in p14ARF-induced human mammary epithelial cell (MEC) senescence (P. Sekaric, V. A. Shamanin, J. Luo, and E. J. Androphy, Oncogene 26:6261-6268, 2007). In this study, we analyzed a set of HPV16 E6 mutants for the ability to induce hAda3 degradation. E6 mutants that degrade hAda3 but not p53 could abrogate p14ARF-induced growth arrest despite the presence of normal levels of p53 and efficiently immortalized MECs. However, two E6 mutants that previously were reported to immortalize MECs with low efficiency were found to be defective for both p53 and hAda3 degradation. We found that these immortal MECs select for reduced p53 protein levels through a proteasome-dependent mechanism. The findings strongly imply that the inactivation of the p14ARF-p53 pathway, either by the E6-mediated degradation of p53 or hAda3 or by cellular adaptation, is required for MEC immortalization.</p>
dc.identifier.submissionpathoapubs/2028
dc.contributor.departmentUniversity of Massachusetts Medical School
dc.source.pages3912-20


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