Centrosomes, genomic instability, and cervical XXXX .

@entity1 @entity5 @entity996 @entity189 @entity876 @entity854 @entity1082 @entity105
High-risk @entity1082 )-associated @entity105 of the uterine cervix is a particularly useful model to study basic mechanisms of genomic instability in @entity5 . Cervical @entity105 is associated with the expression of two high-risk HPV-encoded oncoproteins, E6 and E7. Aneuploidy, the most frequent form of genomic instability in @entity1 @entity189 , develops as early as in nonmalignant cervical precursor lesions. In addition, cervical @entity5 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 @entity854 . 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 @entity996 @entity5 suppressor pathway, can provoke abnormal centrosome duplication in phenotypically normal cells. On the contrary, cells expressing the HPV E6 oncoprotein, which inactivates @entity876 , 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 @entity5 progression.
