Chromosomal instability, one of the most prominent features of tumour cells, causes aneuploidy. Tetraploidy is thought to be an intermediate on the path to aneuploidy, but the mechanistic relationship between the two states is poorly understood. Here, we show that spindle polarity (e.g. bipolarity or multipolarity) in tetraploid cells depends on the level of functional phosphorylated Eg5, a mitotic kinesin, localised to the spindle. Multipolar spindles are formed in cells with high levels of phosphorylated Eg5. This process is suppressed by inhibition of Eg5 or expression of a non-phosphorylatable Eg5 mutant, as well as by changing the balance between opposing forces required for centrosome separation. Tetraploid cells with high levels of functional Eg5 give rise to a heterogeneous aneuploid population through multipolar division, whereas cells with low levels of functional Eg5 continue to undergo bipolar division and remain tetraploid. Furthermore, Eg5 protein levels correlate with ploidy status in tumour specimens. We provide a novel explanation for the tetraploid intermediate model, i.e. spindle polarity and subsequent tetraploid cell behaviour are determined by the balance of forces generated by mitotic kinesins at the spindle.

中文翻译：

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驱动蛋白产生的力平衡控制四倍体细胞中的纺锤体极性和染色体异质性。

染色体不稳定性是肿瘤细胞最突出的特征之一，可引起非整倍性。四倍体被认为是非整倍性途径的中间产物，但是人们对这两种状态之间的机理关系知之甚少。在这里，我们显示四倍体细胞中的纺锤体极性（例如双极性或多极性）取决于功能性磷酸化Eg5（一种有丝分裂驱动蛋白）的水平，该水平定位在纺锤体上。在具有高水平磷酸化Eg5的细胞中形成多极纺锤体。通过抑制Eg5或不可磷酸化的Eg5突变体的表达，以及通过改变中心体分离所需的相反作用力之间的平衡，抑制了这一过程。具有高功能Eg5的四倍体细胞通过多极分裂产生异质非整倍体种群，而具有低水平功能性Eg5的细胞继续经历双极分裂并保持四倍体。此外，Eg5蛋白水平与肿瘤标本中的倍性状态相关。我们为四倍体中间模型提供了新颖的解释，即纺锤体极性和随后的四倍体细胞行为由纺锤体上有丝分裂驱动蛋白产生的力的平衡决定。