title: Regulation of telomerase by human papillomaviruses.
abstract: The E6 oncoprotein of human papillomaviruses (HPVs) induces telomerase activity in primary human epithelial cells. This activity is dependent on association of E6 with E6AP, a cellular ubiquitin ligase. E6 activates the transcription of hTERT, the catalytic subunit of telomerase. E boxes near the start of hTERT transcription are required for E6; however, acetylated histones are only present in the E6 cells. We identified two isoforms of NFX1, a new binding partner of E6/E6AP. The NFX1- 91 isoform binds to an X-box motif located adjacent to the proximal E box, binds Sin3A and HDACs, repressing hTERT transcription. It preferentially binds E6/E6AP and is targeted for ubiquitin-mediated degradation. The NFX1-123 isoform has the opposite activity, increasing hTERT transcription or translation. This is the first example of viral oncoproteins disrupting regulation of telomerase, a critical event in tumorigenesis.
authors.affiliation: Program in Cancer Biology, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Galloway
authors.forename: L C
authors.initials: LC
authors.lastname: Gewin
authors.forename: H
authors.initials: H
authors.lastname: Myers
authors.forename: W
authors.initials: W
authors.lastname: Luo
authors.forename: C
authors.initials: C
authors.lastname: Grandori
authors.forename: R A
authors.initials: RA
authors.lastname: Katzenellenbogen
authors.forename: J K
authors.initials: JK
authors.lastname: McDougall
mesh_terms: D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000821:virology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology; D030361:Papillomavirus Infections / Q000209:etiology; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000209:etiology
chemical_list: D004268:DNA-Binding Proteins; C489427:MYC protein, human; C492666:NFX1 protein, human; D009856:Oncogene Proteins, Viral; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D019098:Telomerase