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

Hiroshi Katayama, Kaori Sasai, Hidehiko Kawai, Zhi Min Yuan, Jolanta Bondaruk, Fumio Suzuki, Satoshi Fujii, Ralph B. Arlinghaus, Bogdan A. Czerniak, Subrata Sen

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalNature Genetics
Volume36
Issue number1
DOIs
Publication statusPublished - Jan 2004
Externally publishedYes

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Aurora Kinase A
Phosphorylation
Ubiquitination
G2 Phase Cell Cycle Checkpoints
Centrosome
Chromosomal Instability
RNA Interference
Urinary Bladder Neoplasms
Cisplatin
Proteolysis

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. / Katayama, Hiroshi; Sasai, Kaori; Kawai, Hidehiko; Yuan, Zhi Min; Bondaruk, Jolanta; Suzuki, Fumio; Fujii, Satoshi; Arlinghaus, Ralph B.; Czerniak, Bogdan A.; Sen, Subrata.

In: Nature Genetics, Vol. 36, No. 1, 01.2004, p. 55-62.

Research output: Contribution to journalArticle

Katayama, H, Sasai, K, Kawai, H, Yuan, ZM, Bondaruk, J, Suzuki, F, Fujii, S, Arlinghaus, RB, Czerniak, BA & Sen, S 2004, 'Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53', Nature Genetics, vol. 36, no. 1, pp. 55-62. https://doi.org/10.1038/ng1279
Katayama, Hiroshi ; Sasai, Kaori ; Kawai, Hidehiko ; Yuan, Zhi Min ; Bondaruk, Jolanta ; Suzuki, Fumio ; Fujii, Satoshi ; Arlinghaus, Ralph B. ; Czerniak, Bogdan A. ; Sen, Subrata. / Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. In: Nature Genetics. 2004 ; Vol. 36, No. 1. pp. 55-62.
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