Abstract
Aurora A is a serine/threonine kinase that functions in various stages of mitosis. Accumulating evidence has demonstrated that gene amplification and overexpression of Aurora A are linked to tumorigenesis, suggesting that Aurora A is an oncogene. In addition, Aurora A overexpression has been used as a negative prognostic marker, because it is associated with resistance to anti-mitotic agents commonly used for cancer therapy. To understand the physiological functions of Aurora A, we generated Aurora A knock-out mice. Aurora A null mice die early during embryonic development before the 16-cell stage. These Aurora A null embryos have defects in mitosis, particularly in spindle assembly, supporting critical functions of Aurora A during mitotic transitions. Interestingly, Aurora A heterozygosity results in a significantly increased tumor incidence in mice, suggesting that Aurora A may also act as a haploinsufficient tumor suppressor. Consistently, Aurora A heterozygous mouse embryonic fibroblasts have higher rates of aneuploidy. We further discovered that VX-680, an Aurora kinase inhibitor currently in phase II clinical trials for cancer treatment, could induce aneuploidy in wild type mouse embryonic fibroblasts. We conclude that a balanced Aurora A level is critical for maintaining genomic stability and one needs to be fully aware of the potential side effects of anti-cancer therapy based on the use of Aurora A-specific inhibitors.
Highlights
Member of Aurora in yeast and two in Drosophila, three were identified in mammals (Aurora A/B/C) with highly conserved catalytic domains [1]
Aurora A targets the CDK1-Cyclin B1 complex to centrosome during prophase [15] and facilitates the activation of this complex by phosphorylating and degrading Cdc25B [13, 19], which is crucial for promoting mitotic entry and nuclear envelop breakdown
VX-680 binds to the ATP binding cleft of the kinase domain, which is shared in all 3 Aurora kinases, inhibiting kinase activity
Summary
Member of Aurora in yeast and two in Drosophila, three were identified in mammals (Aurora A/B/C) with highly conserved catalytic domains [1]. Overexpression of Aurora has been identified in various tumors, and leads to disruption of the spindle checkpoint and causes cells to become resistant to anti-mitotic agents [7, 8, 21]. The death occurred at early stages of embryonic development as no Aurora A null embryos could be obtained at 10.5 day post coitum (Fig. 1c).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
