Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53

Aurora Kinase A (also called STK15 and BTAK) is overexpressed in many human cancers. Ectopic overexpression of Aurora Kinase A in mammalian cells induces centrosome amplification, chromosome instability and oncogenic transformation, a phenotype characteristic of loss-of-function mutations of p53. Here we show that Aurora Kinase A phosphorylates p53 at Ser315, leading to its ubiquitination by MDM2 and proteolysis. p53 is not degraded in the presence of inactive Aurora Kinase A or ubiquitination-defective MDM2. Destabilization of p53 by Aurora Kinase A is abrogated in the presence of mutant MDM2 that is unable to bind p53 and after repression of MDM2 by RNA interference. Silencing of Aurora Kinase A results in less phosphorylation of p53 at Ser315, greater stability of p53 and cell-cycle arrest at G2-M. Cells depleted of Aurora Kinase A are more sensitive to cisplatin-induced Apoptosis, and elevated expression of Aurora Kinase A abolishes this response. In a sample of bladder tumors with wild-type p53, elevated expression of Aurora Kinase A was correlated with low p53 concentration. We conclude that Aurora Kinase A is a key regulatory component of the p53 pathway and that overexpression of Aurora Kinase A leads to increased degradation of p53, causing downregulation of checkpoint-response pathways and facilitating oncogenic transformation of cells.