title: Human papillomaviruses and centrosome duplication errors: modeling the origins of genomic instability.
abstract: The majority of human cancers are genomically unstable, often with gains or losses of whole chromosomes. In high-risk human papillomavirus (HPV)-associated cervical neoplasia, the two HPV-encoded oncoproteins E6 and E7 have been implicated in mitotic infidelity by their ability to induce centrosome-related mitotic disturbances. However, the mechanisms by which HPV E6 and E7 subvert centrosome homeostasis are strikingly different. Whereas the E7 oncoprotein rapidly drives centrosome duplication errors in cells that appear phenotypically normal, expression of the HPV E6 oncoprotein results in an accumulation of supernumerary centrosomes in multinucleated cells. The primary centrosome duplication defect in HPV E7 expressing cells may be linked to the ability of E7 to disrupt regulatory nodes that govern both the host cell division cycle machinery and the initiation of centrosome duplication. Most importantly, the E7 oncoprotein has been shown to dysregulate cdk2 activity, a major determinant for the initiation of centrosome duplication. HPV-induced centrosome abnormalities, multipolar mitoses, and aneuploidy often occur at early stages during cervical carcinogenesis and increase with malignant conversion. These findings suggest that HPV oncoprotein-induced chromosomal instability increases the risk for genetic changes that may ultimately facilitate carcinogenic progression.
authors.affiliation: Department of Pathology, Harvard Medical School, Armenise Research Building, D2-537, 200 Longwood Avenue, Boston, Massachusetts, MA 02115, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D018385:Centrosome; D016678:Genome; D006801:Humans; D027383:Papillomaviridae / Q000502:physiology*; D014779:Virus Replication