The balance of forces generated by kinesins controls spindle polarity and chromosomal heterogeneity in tetraploid cells
The balance of forces generated by kinesins controls spindle polarity and chromosomal heterogeneity in tetraploid cells
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DOI：
10.1242/jcs.231530
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发表时间：
2019-11
影响因子：
4
通讯作者：
S. Shu;M. Iimori;T. Wakasa;K. Ando;H. Saeki;Y. Oda;E. Oki;Y. Maehara
中科院分区：
文献类型：
--
作者：
S. Shu;M. Iimori;T. Wakasa;K. Ando;H. Saeki;Y. Oda;E. Oki;Y. Maehara
摘要染色体不稳定是肿瘤细胞最显著的特征之一，导致非整倍体。四倍体被认为是通向非整倍体的中间环节，但人们对这两种状态之间的机制关系知之甚少。在这里，我们表明，四倍体细胞中纺锤体的两极或多极取决于定位于纺锤体的功能性磷酸化EG5的水平，EG5是一种有丝分裂动蛋白。在高水平磷酸化EG5的细胞中形成多极纺锤体。通过抑制EG5或表达非磷酸化的EG5突变体，以及改变中心体分离所需的相反力量之间的平衡，这一过程被抑制。功能EG5水平高的四倍体细胞通过多极分裂形成异质性非整倍体群体，而功能EG5水平低的细胞继续进行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体状态相关。我们对四倍体中间模型提出了一个新的解释，即纺锤体的极性和随后的四倍体细胞行为是由纺锤体有丝分裂动蛋白产生的力的平衡决定的。摘要：在四倍体细胞中，关键的调节因子EG5及其相关的动蛋白决定着纺锤体的极性、染色体的分离，从而决定非整倍体和染色体的异质性。
ABSTRACT 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. Summary: In tetraploid cells, a key regulator, Eg5, and its related kinesins determine spindle polarity, chromosome segregation and, consequently, aneuploidy and chromosomal heterogeneity.