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

Abstract

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.

• Authors: Hiroshi Katayama, Kaori Sasai, Hidehiko Kawai, Zhi-Min Yuan, Jolanta Bondaruk, Fumio Suzuki, Satoshi Fujii, Ralph B Arlinghaus, Bogdan A Czerniak, Subrata Sen
• Journal: Nature genetics (Nat Genet) Vol. 36 Issue 1 Pg. 55-62 (Jan 2004) ISSN: 1061-4036 [Print] United States
• PMID: 14702041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nuclear Proteins
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• AURKA protein, human
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

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