AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol

被引：530

作者：

Anand, S

Penrhyn-Lowe, S

Venkitaraman, AR

机构：

[1] Univ Cambridge, CR UK Dept Oncol, Cambridge CB2 2XZ, England

[2] Univ Cambridge, MRC Canc Cell Unit, Hutchison MRC Res Ctr, Cambridge CB2 2XZ, England

来源：

CANCER CELL | 2003年 / 3卷 / 01期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1016/S1535-6108(02)00235-0

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The serine-threonine kinase gene AURORA-A is commonly amplified in epithelial malignancies. Here we show that elevated Aurora-A expression at levels that reflect cancer-associated gene amplification overrides the checkpoint mechanism that monitors mitotic spindle assembly, inducing resistance to the chemotherapeutic agent paclitaxel (Taxol). Cells overexpressing Aurora-A inappropriately enter anaphase despite defective spindle formation, and the persistence of Mad2 at the kinetochores, marking continued activation of the spindle assembly checkpoint. Mitosis is subsequently arrested by failure to complete cytokinesis, resulting in multinucleation. This abnormality is relieved by an inhibitory mutant of BUB1, linking the mitotic abnormalities provoked by Aurora-A overexpression to spindle checkpoint activity. Consistent with this conclusion, elevated Aurora-A expression causes resistance to apoptosis induced by Taxol in a human cancer cell line.

引用

收藏

页码：51 / 62

页数：12

相关论文

共 53 条

[1] INCENP binds the Aurora-related kinase AIRK2 and is required to target it to chromosomes, the central spindle and cleavage furrow [J].

Adams, RR ;

Wheatley, SP ;

Gouldsworthy, AM ;

Kandels-Lewis, SE ;

Carmena, M ;

Smythe, C ;

Gerloff, DL ;

Earnshaw, WD .

CURRENT BIOLOGY, 2000, 10 (17) :1075-1078

[2] Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation [J].

Adams, RR ;

Maiato, H ;

Earnshaw, WC ;

Carmena, M .

JOURNAL OF CELL BIOLOGY, 2001, 153 (04) :865-879

[3] The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the, spindle checkpoint [J].

Biggins, S ;

Murray, AW .

GENES & DEVELOPMENT, 2001, 15 (23) :3118-3129

[4] The conserved protein kinase Ipl1 regulates microtubule binding to kinetochores in budding yeast [J].

Biggins, S ;

Severin, FF ;

Bhalla, N ;

Sassoon, I ;

Hyman, AA ;

Murray, AW .

GENES & DEVELOPMENT, 1999, 13 (05) :532-544

[5] A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers [J].

Bischoff, JR ;

Anderson, L ;

Zhu, YF ;

Mossie, K ;

Ng, L ;

Souza, B ;

Schryver, B ;

Flanagan, P ;

Clairvoyant, F ;

Ginther, C ;

Chan, CSM ;

Novotny, M ;

Slamon, DJ ;

Plowman, GD .

EMBO JOURNAL, 1998, 17 (11) :3052-3065

[6] The Aurora/Ipi1p kinase family: regulators of chromosome segregation and cytokinesis [J].

Bischoff, JR ;

Plowman, GD .

TRENDS IN CELL BIOLOGY, 1999, 9 (11) :454-459

[7] Characterization of MAD2B and other mitotic spindle checkpoint genes [J].

Cahill, DP ;

da Costa, LT ;

Carson-Walter, EB ;

Kinzler, KW ;

Vogelstein, B ;

Lengauer, C .

GENOMICS, 1999, 58 (02) :181-187

[8] Mutations of mitotic checkpoint genes in human cancers [J].

Cahill, DP ;

Lengauer, C ;

Yu, J ;

Riggins, GJ ;

Willson, JKV ;

Markowitz, SD ;

Kinzler, KW ;

Vogelstein, B .

NATURE, 1998, 392 (6673) :300-303

[9]

CHAN CSM, 1993, GENETICS, V135, P677

[10] Mitotic phosphorylation of histone H3: Spatio-temporal regulation by mammalian aurora kinases [J].

Crosio, C ;

Fimia, GM ;

Loury, R ;

Kimura, M ;

Okano, Y ;

Zhou, HY ;

Sen, S ;

Allis, CD ;

Sassone-Corsi, P .

MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (03) :874-885

← 1 2 3 4 5 6 →