Modulated microtubule dynamics enable Hklp2/Kif15 to assemble bipolar spindles
Modulated microtubule dynamics enable Hklp2/Kif15 to assemble bipolar spindles
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DOI：
10.4161/cc.10.20.17817
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发表时间：
2011-10-15
期刊：
影响因子：
4.3
通讯作者：
Mayer, Thomas U.
中科院分区：
文献类型：
--
作者：
Florian, Stefan;Mayer, Thomas U.
滑动电机EG5的活动和协调的微管动力学都是有丝分裂纺锤体极分离所必需的。微管动力学的改变是否能补偿EG5活性的抑制并重新使之复极化仍是一个有争议的问题。使用一致的活细胞成像方法，我们发现微管动力学的扰动可以通过纺锤体形成过程补偿EG5的抑制，这一过程使人想起减数分裂：在EG5抑制的哺乳动物体细胞中，通过耗尽TOGp或低剂量的诺可达唑导致微管动力学的改变，诱导形成多个无着丝体纺锤体极，这些纺锤体极经过中间多极状态，然后是双极。极点分离依赖于HKLP2/Kif15，这是一种本来是可有可无的正端定向主轴电机，导致主轴带有两个中心体极。一旦双极，纺锤体不再依赖改变的微管动力学来维持其双极，并在染色体分离中发挥作用。我们得出结论，改变的微管动力学使HKLP2/Kif15能够通过一种涉及无着丝体极点形成的机制来取代EG5进行极分离。我们的观察表明，使用微管靶向药物和EG5抑制剂的联合化疗方案可能不如预期的有效。
Activity of the sliding motor Eg5 and coordinated microtubule dynamics are both essential for mitotic spindle pole separation. It is still a matter of controversy if changes in microtubule dynamics can compensate inhibition of Eg5 activity and re-enable bipolarization. Using a consistent live-cell-imaging approach, we show that perturbation of microtubule dynamics can compensate inhibition of Eg5 through a spindle formation process reminiscent of meiosis: In Eg5-inhibited mammalian somatic cells, alteration of microtubule dynamics through depletion of TOGp or low doses of nocodazole induces the formation of multiple acentrosomal spindle poles which pass through an intermediate multipolar state followed by bipolarization. Pole separation depends on Hklp2/Kif15, an otherwise dispensable plus-end directed spindle motor and results in spindles with two centrosomal poles. Once bipolar, spindles do not rely on altered microtubule dynamics to maintain their bipolarity anymore and are functional in chromosome segregation. We conclude that altered microtubule dynamics enable Hklp2/Kif15 to replace Eg5 in pole separation through a mechanism involving the formation of acentrosomal poles. Our observations suggest that combination chemotherapy regimens involving microtubule-targeting drugs and Eg5 inhibitors might be less effective than expected.