title: Human papillomavirus type 16 E7 oncoprotein associates with E2F6.
abstract: The papillomavirus life cycle is intimately coupled to the differentiation state of the infected epithelium. Since papillomaviruses lack most of the rate-limiting enzymes required for genome synthesis, they need to uncouple keratinocyte differentiation from cell cycle arrest and maintain or reestablish a replication-competent state within terminally differentiated keratinocytes. The human papillomavirus (HPV) E7 protein appears to be a major determinant for this activity and induces aberrant S-phase entry through the inactivation of the retinoblastoma tumor suppressor and related pocket proteins. In addition, E7 can abrogate p21 and p27. Together, this leads to the activation of E2F1 to E2F5, enhanced expression of E2F-responsive genes, and increased cdk2 activity. E2F6 is a pRB-independent, noncanonical member of the E2F transcription factor family that acts as a transcriptional repressor. E2F6 expression is activated in S phase through an E2F-dependent mechanism and thus may provide a negative-feedback mechanism that slows down S-phase progression and/or exit in response to the activation of the other E2F transcription factors. Here, we show that low- and high-risk HPV E7 proteins, as well as simian virus 40 T antigen and adenovirus E1A, can associate with and inactivate the transcriptional repression activity of E2F6, thereby subverting a critical cellular defense mechanism. This may result in the extended S-phase competence of HPV-infected cells. E2F6 is a component of polycomb group complexes, which bind to silenced chromatin and are critical for the maintenance of cell fate. We show that E7-expressing cells show decreased staining for E2F6/polycomb complexes and that this is at least in part dependent on the association with E2F6.
authors.affiliation: Department of Medicine, Infectious Diseases Division, The Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin-Drubin
authors.forename: Kyung-Won
authors.initials: KW
authors.lastname: Huh
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D050684:E2F Transcription Factors / Q000378:metabolism*; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D010957:Plasmids; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013539:Simian virus 40 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D017500:Adenovirus E1A Proteins; D000957:Antigens, Viral, Tumor; D050684:E2F Transcription Factors; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D008156:Luciferases