Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73

Cancer Cell. 2012 Feb 14;21(2):196-211. doi: 10.1016/j.ccr.2011.12.025.

Abstract

Elevated Aurora kinase-A expression is correlated with abrogation of DNA damage-induced apoptotic response and mitotic spindle assembly checkpoint (SAC) override in human tumor cells. We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. Aurora-A phosphorylated p73 also facilitates inactivation of SAC through dissociation of the MAD2-CDC20 complex in cells undergoing mitosis. Cells expressing phosphor-mimetic mutant (S235D) of p73 manifest altered growth properties, resistance to cisplatin- induced apoptosis, as well as premature dissociation of the MAD2-CDC20 complex, and accelerated mitotic exit with SAC override in the presence of spindle damage. Elevated cytoplasmic p73 in Aurora-A overexpressing primary human tumors corroborates the experimental findings.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Aurora Kinase A
  • Aurora Kinases
  • DNA Damage*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • M Phase Cell Cycle Checkpoints*
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Pancreatic Neoplasms / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology*

Substances

  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • Nuclear Proteins
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • mortalin
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases