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

Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
Cancer cell (Impact Factor: 23.89). 02/2012; 21(2):196-211. DOI: 10.1016/j.ccr.2011.12.025
Source: PubMed

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.

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May 17, 2014