TY - JOUR
T1 - Aurora Kinase-A Inactivates DNA Damage-Induced Apoptosis and Spindle Assembly Checkpoint Response Functions of p73
AU - Katayama, Hiroshi
AU - Wang, Jin
AU - Treekitkarnmongkol, Warapen
AU - Kawai, Hidehiko
AU - Sasai, Kaori
AU - Zhang, Hui
AU - Wang, Hua
AU - Adams, Henry P.
AU - Jiang, Shoulei
AU - Chakraborty, Sandip N.
AU - Suzuki, Fumio
AU - Arlinghaus, Ralph B.
AU - Liu, Jinsong
AU - Mobley, James A.
AU - Grizzle, William E.
AU - Wang, Huamin
AU - Sen, Subrata
N1 - Funding Information:
The authors thank Dr. Zhi-Min Yuan for the GFP-tagged p73 expression construct and luciferase reporter constructs, Dr. Elsa Flores for the HA-tagged p73 expression constructs, Dr. Kenji Fukasawa for the mortalin expression constructs, Dr. Richard Behringer for the mCherry vector, and Dr. Mei Leng for the GFP-H2B-expressing HeLa cells. We acknowledge the technical assistance of Ms. Yvette Gonzales and Ms. Aimee LeBlanc. Editorial help of Ms Amy Sutton from the Department of Scientific Publications is acknowledged. This study was supported by grants awarded to S.S. from the National Institutes of Health (R01CA089716 and NCI/EDRN UO1CA111302), the University Cancer Foundation, and the M.D. Anderson Cancer Center. The DNA analysis facility used in the study is supported by Cancer Center Support Grant CA16672. UAB Pancreatic SPORE (5P50CA0101955) supported W.E.G. and J.A.M.
PY - 2012/2/14
Y1 - 2012/2/14
N2 - 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.
AB - 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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U2 - 10.1016/j.ccr.2011.12.025
DO - 10.1016/j.ccr.2011.12.025
M3 - Article
C2 - 22340593
AN - SCOPUS:84863046504
SN - 1535-6108
VL - 21
SP - 196
EP - 211
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -
