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.
Mesh Terms:
Apoptosis, Cell Cycle, Humans, Nuclear Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Nat. Genet.
Date: Jan. 01, 2004
Download 5 Interactions For This Publication
111010
Switch View:
  • Interactions 5
  • PTM Genes 1