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.
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Acknowledgements
We are grateful to Anette Duensing for critical reading of the manuscript, M Ericsson for performing electron microscopy and M Bornens for sharing reagents. Work in the authors' laboratory is supported by Public Health Service Grants R01 CA81135, R01 CA66980, and P01 DE00275 (K Münger) and a fellowship from the Deutsche Forschungsgemeinschaft (S Duensing).
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Duensing, S., Münger, K. Human papillomaviruses and centrosome duplication errors: modeling the origins of genomic instability. Oncogene 21, 6241–6248 (2002). https://doi.org/10.1038/sj.onc.1205709
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DOI: https://doi.org/10.1038/sj.onc.1205709
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