title: The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle.
abstract: Loss of genomic integrity is a defining feature of many human malignancies, including human papillomavirus (HPV)-associated preinvasive and invasive genital squamous lesions. Here we show that aberrant mitotic spindle pole formation caused by abnormal centrosome numbers represents an important mechanism in accounting for numeric chromosomal alterations in HPV-associated carcinogenesis. Similar to what we found in histopathological specimens, HPV-16 E6 and E7 oncoproteins cooperate to induce abnormal centrosome numbers, aberrant mitotic spindle pole formation, and genomic instability. The low-risk HPV-6 E6 and E7 proteins did not induce such abnormalities. Whereas the HPV-16 E6 oncoprotein has no immediate effects on centrosome numbers, HPV-16 E7 rapidly induces abnormal centrosome duplication. Thus our results suggest a model whereby HPV-16 E7 induces centrosome-related mitotic disturbances that are potentiated by HPV-16 E6.
authors.affiliation: Department of Pathology and Harvard Center for Cancer Biology, Solid Tumor Cytogenetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Duensing
authors.forename: L Y
authors.initials: LY
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Duensing
authors.forename: J
authors.initials: J
authors.lastname: Basile
authors.forename: S
authors.initials: S
authors.lastname: Piboonniyom
authors.forename: S
authors.initials: S
authors.lastname: Gonzalez
authors.forename: C P
authors.initials: CP
authors.lastname: Crum
authors.forename: K
authors.initials: K
authors.lastname: Munger
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018385:Centrosome / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D008938:Mitosis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D008941:Spindle Apparatus / Q000235:genetics; D014407:Tumor Cells, Cultured; D014846:Vulvar Neoplasms / Q000235:genetics / Q000821:virology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16