Aurora-A Genetic Variants and their Oncogenic Activity

Target Discovery and Apoptosis Team

Section: Cancer Research UK Cancer Therapeutics Unit

Human cancer susceptibility is, in part, due to the presence of rare mutations or polymorphisms in genes that have major effects on tumour growth or survival. These 'high-penetrance' mutations in genes such as the breast cancer susceptibility gene BRCA1/2 are responsible for a proportion of familial cancers. However, the genetic basis of susceptibility to the majority of cancers that have no obvious familial aggregation is almost completely unknown. The detection of 'low-penetrance' genetic variants in studies of the human population is difficult due to genetic heterogeneity. Biochemical, genetic and clinical data have implicated Aurora-A in cancer.

Furthermore, we recently showed that a common polymorphic variant in the human Aurora-A gene (Ile-31) is preferentially amplified in colon tumours, and is associated with increased aneuploidy. Using the yeast two-hybrid system as a tool to isolate binding partners of the two polymorphic forms of the Aurora-A protein at the 31 amino acid, we identified the E2 ubiquitin conjugating enzyme UBE2N as a specific binding partner of the 'weak' Phe-31 variant form. In vitro and in vivo data showed that the Aurora-S Phe-31 isoform interacts via the N-amino terminal domain with Ubc13. In addition, UBE2N co-localises with Aurora-A at the centrosomes in 293 cells. Biochemically, this interaction results in ubiquitination of Aurora-A and these alterations potentially play a distinct role in cell growth and tumour development.

We are continuing work on this pathway to identify its constituent components. The Ile-31 variant that is preferentially amplified in tumours transforms rat 1 cells more potently than the more common Phe-31 variant allele. These results are consistent with an important role for the Ile-31 variant of Aurora-A in human cancer susceptibility. Finally, understanding the molecular basis of Aurora-A regulation will be important in the identification of novel targets for new cancer treatments.