title: Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.
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.
authors.affiliation: Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katayama
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Warapen
authors.initials: W
authors.lastname: Treekitkarnmongkol
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kawai
authors.forename: Kaori
authors.initials: K
authors.lastname: Sasai
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Henry P
authors.initials: HP
authors.lastname: Adams
authors.forename: Shoulei
authors.initials: S
authors.lastname: Jiang
authors.forename: Sandip N
authors.initials: SN
authors.lastname: Chakraborty
authors.forename: Fumio
authors.initials: F
authors.lastname: Suzuki
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Arlinghaus
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: James A
authors.initials: JA
authors.lastname: Mobley
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
mesh_terms: D017209:Apoptosis; D064096:Aurora Kinase A; D064127:Aurora Kinases; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C080352:mortalin; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases