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

Academic Article

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.
  • Published In

  • Cancer Cell  Journal
  • Keywords

  • Apoptosis, Aurora Kinase A, Aurora Kinases, DNA Damage, DNA-Binding Proteins, HSP70 Heat-Shock Proteins, Humans, M Phase Cell Cycle Checkpoints, Nuclear Proteins, Pancreatic Neoplasms, Phosphorylation, Protein-Serine-Threonine Kinases, Tumor Cells, Cultured, Tumor Protein p73, Tumor Suppressor Proteins
  • Digital Object Identifier (doi)

    Author List

  • Katayama H; Wang J; Treekitkarnmongkol W; Kawai H; Sasai K; Zhang H; Wang H; Adams HP; Jiang S; Chakraborty SN
  • Start Page

  • 196
  • End Page

  • 211
  • Volume

  • 21
  • Issue

  • 2