Centrosomes, genomic instability, and cervical carcinogenesis.
High-risk human papillomavirus (HPV)-associated carcinogenesis of the uterine cervix is a particularly useful model to study basic mechanisms of genomic instability in cancer. Cervical carcinogenesis is associated with the expression of two high-risk HPV-encoded oncoproteins, E6 and E7. Aneuploidy, the most frequent form of genomic instability in human carcinomas, develops as early as in nonmalignant cervical precursor lesions. In addition, cervical neoplasia is frequently associated with abnormal multipolar mitotic figures, suggesting disturbances of the cell-division process as a mechanism for chromosome segregation defects. Spindle poles are formed by centrosomes, and the high-risk HPV E6 and E7 oncoproteins can each induce abnormal centrosome numbers. These two HPV oncoproteins, however, induce centrosome abnormalities through fundamentally different mechanisms and, presumably, with different functional consequences. High-risk HPV E7, which targets the pRB tumor suppressor pathway, can provoke abnormal centrosome duplication in phenotypically normal cells. On the contrary, cells expressing the HPV E6 oncoprotein, which inactivates p53, accumulate abnormal numbers of centrosomes in parallel with multinucleation and nuclear atypia. These two pathways are not mutually exclusive, since co-expression of HPV E6 and E7 has synergistic effects on centrosome abnormalities and chromosomal instability. Taken together, these findings support the general model in which chromosomal instability arises as a direct consequence of oncogenic insults and can develop at early stages of tumor progression.
Duensing
Stefan
S
Harvard Medical School, Department of Pathology, Armenise 537, 200 Longwood Avenue, Boston, MA 02115, USA. stefan_duensing@hms.harvard.edu
Münger
Karl
K
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D018385:Centrosome / Q000502:physiology*; D043171:Chromosomal Instability; D005260:Female; D006801:Humans; D008957:Models, Genetic; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology
D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53