Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnologies, Sapienza University of Rome, Via degli Apuli 4, Rome, Italy.
Mol Cancer. 2011 Oct 19;10:131. doi: 10.1186/1476-4598-10-131.
Aurora-A is an oncogenic kinase playing well-documented roles in mitotic spindle organisation. We previously found that Aurora-A inactivation yields the formation of spindles with fragmented poles that can drive chromosome mis-segregation. Here we have addressed the mechanism through which Aurora-A activity regulates the structure and cohesion of spindle poles.
We inactivated Aurora-A in human U2OS osteosarcoma cells either by RNA-interference-mediated silencing or treating cultures with the specific inhibitor MLN8237. We show that mitotic spindle pole fragmentation induced by Aurora-A inactivation is associated with microtubule hyperstabilisation. Silencing of the microtubule-stabilising factor ch-TOG prevents spindle pole fragmentation caused by inactivation of Aurora-A alone and concomitantly reduces the hyperstabilisation of microtubules. Furthermore, decreasing pole-directed spindle forces by inhibition of the Eg5 kinesin, or by destabilisation of microtubule-kinetochore attachments, also prevents pole fragmentation in Aurora-A-inactivated mitoses.
Our findings indicate that microtubule-generated forces are imbalanced in Aurora-A-defective cells and exert abnormal pressure at the level of spindle poles, ultimately causing their fragmentation. This study therefore highlights a novel role of the Aurora-A kinase in regulating the balance between microtubule forces during bipolar spindle assembly.
Aurora-A 是一种致癌激酶，在有丝分裂纺锤体组织中发挥着有充分文献记载的作用。我们之前发现，Aurora-A 的失活会导致纺锤体极碎片化，从而导致染色体错误分离。在这里，我们研究了 Aurora-A 活性调节纺锤体极结构和内聚力的机制。
我们通过 RNA 干扰介导的沉默或用特异性抑制剂 MLN8237 处理培养物，在人 U2OS 骨肉瘤细胞中使 Aurora-A 失活。我们表明，Aurora-A 失活诱导的有丝分裂纺锤体极碎片化与微管超稳定化有关。沉默微管稳定因子 ch-TOG 可防止 Aurora-A 失活单独引起的纺锤体极碎片化，并同时降低微管的超稳定化。此外，通过抑制 Eg5 动力蛋白或破坏微管-动粒连接来降低极向纺锤体力，也可以防止 Aurora-A 失活有丝分裂中的极碎片化。
我们的发现表明，在 Aurora-A 缺陷细胞中，微管产生的力失去平衡，并在纺锤体极水平上施加异常压力，最终导致极碎片化。因此，这项研究突出了 Aurora-A 激酶在调节双极纺锤体组装过程中微管力平衡方面的新作用。
