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

Cancer cell | Feb 14, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22340593

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.

Pubmed ID: 22340593 RIS Download

Mesh terms: 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 Suppressor Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: 5P30CA0101955
  • Agency: NCI NIH HHS, Id: CA16872
  • Agency: NCI NIH HHS, Id: P20 CA101955
  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: P50 CA101955
  • Agency: NCI NIH HHS, Id: R01 CA089716
  • Agency: NCI NIH HHS, Id: R01 CA089716-06
  • Agency: NCI NIH HHS, Id: R01 CA089716-07
  • Agency: NCI NIH HHS, Id: R01 CA089716-08
  • Agency: NCI NIH HHS, Id: R01CA089716
  • Agency: NCI NIH HHS, Id: U01 CA111302
  • Agency: NCI NIH HHS, Id: U01CA111302

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