Functional Analysis and Aurora-A Regulation

Target Discovery and Apoptosis Team

Section: Cancer Research UK Cancer Therapeutics Unit

Mitosis is the most structurally dynamic phase of the cell cycle during which a large number of events occur, including the maturation and separation of the centrosomes and reorganisation of the microtubule network. However, regulators of G2/M phase progression have been found to be altered only infrequently in tumour cells and consequently are much less implicated in tumorigenesis. This appears to be paradoxical in view of the fact that the majority of tumour types reveal numerical chromosomal anomalies or aneuploidy. The mammalian Aurora kinases are associated with interphase centrosomes, the mitotic spindle poles, the mitotic microtubules and the spindle midbody. This is consistent with the possibility that these kinases may play pivotal roles in controlling chromosomal ploidy in cells. Overexpression of Aurora-A has been shown to cause tumorigenic transformation of human and rodent cells in vitro and in vivo.

These findings have for the first time implicated an oncogenic role for an overexpressed mitotic regulator. Aurora-A has been shown to be involved in two main parts of mitosis: in recruiting proteins to the centrosome to ensure centrosome maturation and in the metaphase/anaphase transition by interfering with the anaphase promoting complex (APC)-dependent proteolytic machinery. The exact mechanism of the Aurora-A pathway in these processes remains unclear. We aim to further understand the role of Aurora-A in mitotic control and use this information: (i) to identify mitotic regulators as potential molecular markers in the drug development process and (ii) to identify and validate new targets for cancer therapy.