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dc.contributor.authorShamanin, Vladimir A.
dc.contributor.authorAndrophy, Elliot J.
dc.date2022-08-11T08:09:33.000
dc.date.accessioned2022-08-23T16:35:25Z
dc.date.available2022-08-23T16:35:25Z
dc.date.issued2004-02-18
dc.date.submitted2009-03-24
dc.identifier.citationMol Cell Biol. 2004 Mar;24(5):2144-52.
dc.identifier.issn0270-7306 (Print)
dc.identifier.pmid14966292
dc.identifier.urihttp://hdl.handle.net/20.500.14038/38555
dc.description.abstractInactivation of the ARF-p53 tumor suppressor pathway leads to immortalization of murine fibroblasts. The role of this pathway in immortalization of human epithelial cells is not clear. We analyzed the functionality of the p14(ARF)-p53 pathway in human mammary epithelial cells (MEC) immortalized by human papillomavirus 16 (HPV16) E6, the p53 degradation-defective E6 mutant Y54D, or hTERT. E6-MEC or E6Y54D-MEC maintains high-level expression of p14(ARF). Late-passage hTERT-immortalized MEC express p53 but down-regulate p14(ARF). Enforced expression of p14(ARF) induces p53-dependent senescence in hTERT-MEC, while both E6-MEC and E6Y54D-MEC are resistant. We show that E6Y54D inhibits p14(ARF)-induced activation of p53 without inactivation of the p53-dependent DNA damage response. Hence, p53 degradation and inhibition of p14(ARF) signaling to p53 are independent functions of HPV16 E6. Our observations imply that long-term proliferation of MEC requires inactivation of the p14(ARF)-p53 pathway.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=14966292&dopt=Abstract">Link to Article in PubMed</a>
dc.subjectCell Aging
dc.subject*Cell Transformation, Neoplastic
dc.subjectCells, Cultured
dc.subjectCyclin-Dependent Kinase Inhibitor p16
dc.subjectCyclin-Dependent Kinase Inhibitor p21
dc.subjectCyclins
dc.subjectDNA Damage
dc.subjectDNA-Binding Proteins
dc.subjectEnzyme Inhibitors
dc.subjectEpithelial Cells
dc.subjectGene Expression Regulation
dc.subjectHumans
dc.subjectMammary Glands, Human
dc.subjectOncogene Proteins, Viral
dc.subject*Repressor Proteins
dc.subjectSignal Transduction
dc.subjectTelomerase
dc.subjectTumor Suppressor Protein p14ARF
dc.subjectTumor Suppressor Protein p53
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleImmortalization of human mammary epithelial cells is associated with inactivation of the p14ARF-p53 pathway
dc.typeJournal Article
dc.source.journaltitleMolecular and cellular biology
dc.source.volume24
dc.source.issue5
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2422&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/1423
dc.identifier.contextkey794920
refterms.dateFOA2022-08-23T16:35:25Z
html.description.abstract<p>Inactivation of the ARF-p53 tumor suppressor pathway leads to immortalization of murine fibroblasts. The role of this pathway in immortalization of human epithelial cells is not clear. We analyzed the functionality of the p14(ARF)-p53 pathway in human mammary epithelial cells (MEC) immortalized by human papillomavirus 16 (HPV16) E6, the p53 degradation-defective E6 mutant Y54D, or hTERT. E6-MEC or E6Y54D-MEC maintains high-level expression of p14(ARF). Late-passage hTERT-immortalized MEC express p53 but down-regulate p14(ARF). Enforced expression of p14(ARF) induces p53-dependent senescence in hTERT-MEC, while both E6-MEC and E6Y54D-MEC are resistant. We show that E6Y54D inhibits p14(ARF)-induced activation of p53 without inactivation of the p53-dependent DNA damage response. Hence, p53 degradation and inhibition of p14(ARF) signaling to p53 are independent functions of HPV16 E6. Our observations imply that long-term proliferation of MEC requires inactivation of the p14(ARF)-p53 pathway.</p>
dc.identifier.submissionpathoapubs/1423
dc.contributor.departmentDepartment of Medicine
dc.source.pages2144-52


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