Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.
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.
Mesh Terms:
Apoptosis, 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
Apoptosis, 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
Cancer Cell
Date: Feb. 14, 2012
PubMed ID: 22340593
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