TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity

被引:110
|
作者
Tomasini, Richard [1 ,2 ]
Tsuchihara, Katsuya [1 ,3 ]
Tsuda, Chiharu [4 ]
Lau, Suzanne K. [5 ]
Wilhelm, Margareta [1 ]
Ruffini, Alessandro [1 ]
Tsao, Ming-Sound [5 ]
Iovanna, Juan L. [2 ]
Jurisicova, Andrea [4 ]
Melino, Gerry [6 ,7 ]
Mak, Tak W. [1 ]
机构
[1] Princess Margaret Hosp, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2C1, Canada
[2] INSERM, Unite 624, F-13258 Marseille 9, France
[3] Natl Canc Ctr Hosp E, Res Ctr Innovat Oncol, Chiba 2778577, Japan
[4] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Toronto, ON M5G 2C1, Canada
[5] Univ Toronto, Dept Med Biophys, Div Appl Mol Oncol, Ontario Canc Inst, Toronto, ON M5G 2C4, Canada
[6] Univ Roma Tor Vergata, Biochem IDI IRCCS Lab, I-00133 Rome, Italy
[7] MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England
关键词
Bub1; meiosis; mitotic arrest; p73; spindle checkpoint; MITOTIC CHECKPOINT; TUMOR-SUPPRESSOR; CHROMOSOME INSTABILITY; GENOMIC INSTABILITY; CANCER; P53; ANEUPLOIDY; P73; MICE; MAD2;
D O I
10.1073/pnas.0812096106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.
引用
收藏
页码:797 / 802
页数:6
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