Centrosome abnormalities and genomic instability induced by human papillomavirus oncoproteins.
Cervical cancer is tightly associated with infection by high-risk human papillomaviruses (HPVs). Many high-risk HPV-positive lesions are genomically unstable and show chromosomal gains and losses already at early stages of carcinogenic progression. These genomic aberrations are caused by the HPV-encoded oncoproteins E6 and E7, which subvert mitotic fidelity of the infected host cell. Whereas E7 drives genomic instability by inducing abnormal centrosome numbers, E6 cooperates with E7 presumably by relaxing critical checkpoint control mechanisms. The ability of E7 to induce centrosome duplication errors (CDEs) may be linked to the re-programming of the host cell cycle machinery, including dysregulation of cyclin/cyclin-dependent kinase (cdk) 2 activity. Given the role of cdk2 as a regulatory node not only for cell cycle progression but also for centrosome duplication, inhibition of cdk2 may not only retard cellular proliferation but also decrease CDEs and centrosome-related mitotic defects. Compared to some conventional cytotoxic agents, which exclusively target DNA replication, modulation of cdk2 activity may hold the promise of diminishing the development of genomically unstable, aneuploid tumor cells that are frequently the source of chemotherapy resistance in malignant tumors.
Department of Pathology, Harvard Center for Cancer Biology, Harvard Medical School, Armenise Research Building, D2-537, 200 Longwood Avenue, Boston, MA 02115, USA.
Stefan
S
Duensing
Karl
K
Münger
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018385:Centrosome / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2; D018816:Genes, cdc / Q000502:physiology; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000821:virology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity
D009856:Oncogene Proteins, Viral; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2