The family of Aurora kinases consists of three members (Aurora-A, -B and -C), which have been implicated in the control and regulation of mitotic processes. Erroneous mitosis can lead to chromosomal aberrations and subsequently to aneuploidy. During this process genetic information can be gained or lost, resulting in abnormal levels of regulatory molecules, a major step in carcinogenesis. In multiple types of tumors Aurora kinases have been found overexpressed, highlighting their potential involvement in tumor formation and -progression. These high protein levels have been proposed to be responsible for chromosomal instability and the deactivation of cell cycle checkpoints, which ensure the correct separation and distribution of chromosomes during cell division. Aurora kinases have therefore been regarded as oncogenes. Accordingly, colony formation assays in previous studies show that Aurora-A was effective in transforming rodent cells.
In contrast, Aurora-A has recently been reported to be involved in differentiation processes in D. melanogaster and implicated in tumor suppression. This finding foremost raises questions about the role Aurora-A plays in carcinogenesis. This study investigated the effect of Aurora-A and -C overexpression on normal cells. While Aurora-C showed no effect on normal cells, it was discovered that overexpression of Aurora-A caused inhibition of cell growth. This effect was attributed to a growth arrest in G1-phase of the cell cycle. Microarray data suggested that this arrest was triggered by attenuation of Cyclin D1-dependent pathways, as could also be observed by monitoring phosphorylation of the retinoblastoma gene product. Ectopic expression of Cyclin D1 by adenoviral infection was sufficient to overcome the cell cycle arrest in G1. Cyclin D1-mediated rescue of an Aurora-A-induced G1-block did not affect cell proliferation. Instead, cells underwent a second cell cycle arrest in G2/M-phase. Expression of a dominant negative p53 variant allowed progression through mitosis and resulted in incorrect cell division, confirming earlier reports which linked aneuploidization by Aurora-A to a defective p53 pathway. In conclusion it was shown that Aurora-A overexpression can be a factor driving aneuploidization.
However, two important pathways need to be deregulated - the Rb-dependent restriction point at the G1/S-transition and the p53 pathway, allowing escape from an Aurora-A induced G2/M-block.