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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.

Pubmed ID: 14702041


  • Katayama H
  • Sasai K
  • Kawai H
  • Yuan ZM
  • Bondaruk J
  • Suzuki F
  • Fujii S
  • Arlinghaus RB
  • Czerniak BA
  • Sen S


Nature genetics

Publication Data

January 31, 2004

Associated Grants


Mesh Terms

  • Apoptosis
  • Aurora Kinase A
  • Aurora Kinases
  • Cell Cycle
  • Humans
  • Nuclear Proteins
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-mdm2
  • Tumor Suppressor Protein p53