Aberrant activation of cell cycle regulators, centrosome amplification, and mitotic defects.

The centrosome that functions as a microtubule organizing center of a cell plays a key role in formation of bipolar mitotic spindles. Cells normally have either one (unduplicated) or two (duplicated) centrosomes. However, loss of the mechanisms controlling the numeral integrity of centrosomes leads to centrosome amplification (presence of more than two centrosomes), primarily via overduplication or fragmentation of centrosomes, resulting in defective mitosis and consequentially chromosome instability. Centrosome amplification frequently occurs in various cancers, and is considered as a major cause of chromosome instability. It has recently been found that ROCK2 kinase plays a critical role in promotion of centrosome duplication and amplification. Considering that ROCK2 is activated by Rho protein, and Rho is the immediate downstream target of many growth and hormone receptors, it is possible that such receptors may rather directly affect centrosome duplication and amplification. Indeed, constitutive activation of the receptors known to signal to the Rho pathway leads to promotion of centrosome amplification and chromosome instability in the Rho-ROCK2 pathway-dependent manner. These observations reveal an unexplored, yet important, oncogenic activities of those receptors in carcinogenesis; destabilizing chromosomes through promotion of centrosome amplification via continual activation of the Rho-ROCK2 pathway.