Centrosome abnormalities and genomic instability induced by human papillomavirus oncoproteins.

Abstract

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.