AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol
AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol
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DOI：
10.1016/s1535-6108(02)00235-0
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发表时间：
2003-01-01
期刊：
影响因子：
50.3
通讯作者：
Venkitaraman, AR
中科院分区：
文献类型：
--
作者：
Anand, S;Penrhyn-Lowe, S;Venkitaraman, AR
丝氨酸苏氨酸激酶基因Aurora-A在上皮性恶性肿瘤中常被扩增。在这里，我们表明，在反映癌症相关基因放大水平的Aurora-A表达增加，推翻了监测有丝分裂纺锤体组装的检查点机制，诱导对化疗药物紫杉醇(紫杉醇)的耐药性。过表达Aurora-A的细胞不适当地进入后期，尽管纺锤体形成有缺陷，并且MAD2持续存在于动粒，标志着纺锤体组装检查点的持续激活。有丝分裂随后因未能完成胞质分裂而停止，导致多核。这种异常可以被Bub1的抑制性突变体缓解，该突变体将Aurora-A过度表达引起的有丝分裂异常与纺锤体检查点活动联系起来。与这一结论一致的是，Aurora-A的高表达导致对紫杉醇诱导的人类癌细胞株的凋亡产生抵抗。
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.