Department of Microbiology and Physiological Systems and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Curr Biol. 2012 Feb 7;22(3):225-30. doi: 10.1016/j.cub.2011.12.022. Epub 2012 Jan 19.
During mitosis, equal segregation of chromosomes depends on proper kinetochore-microtubule attachments. Merotelic kinetochore orientation, in which a single kinetochore binds microtubules from both spindle poles [1], is a major cause of chromosome instability [2], which is commonly observed in solid tumors [3, 4]. Using the fission yeast Schizosaccharomyces pombe, we show that a proper force balance between kinesin motors on interpolar spindle microtubules is critical for correcting merotelic attachments. Inhibition of the plus-end-directed spindle elongation motors kinesin-5 (Cut7) and kinesin-6 (Klp9) reduces spindle length, tension at kinetochores, and the frequency of merotelic attachments. In contrast, merotely is increased by deletion of the minus-end-directed kinesin-14 (Klp2) or overexpression of Klp9. Also, Cdk1 regulates spindle elongation forces to promote merotelic correction by phosphorylating and inhibiting Klp9. The role of spindle elongation motors in merotelic correction is conserved, because partial inhibition of the human kinesin-5 homolog Eg5 using the drug monastrol reduces spindle length and lagging chromosome frequency in both normal (RPE-1) and tumor (CaCo-2) cells. These findings reveal unexpected links between spindle forces and correction of merotelic attachments and show that pharmacological manipulation of spindle elongation forces might be used to reduce chromosome instability in cancer cells.
在有丝分裂过程中，染色体的均等分离依赖于动粒微管的正确连接。微管的动粒呈桥联（merotelic）取向，即一个动粒与来自纺锤体两极的微管相连[1]，这是染色体不稳定的一个主要原因[2]，在实体瘤中经常观察到[3,4]。我们利用裂殖酵母 Schizosaccharomyces pombe 表明，在极性纺锤体微管上的驱动蛋白马达之间存在适当的力平衡对于纠正桥联连接至关重要。抑制纺锤体延伸的正向导向马达（kinesin-5，Cut7 和 kinesin-6，Klp9）会减少纺锤体长度、动粒张力和桥联连接的频率。相比之下，缺失负向导向的驱动蛋白-14（Klp2）或过表达 Klp9 会增加桥联。此外，Cdk1 通过磷酸化和抑制 Klp9 来调节纺锤体延伸力以促进桥联的纠正。纺锤体延伸马达在桥联纠正中的作用是保守的，因为使用药物长春碱部分抑制人类驱动蛋白-5 同源物 Eg5，可减少正常（RPE-1）和肿瘤（CaCo-2）细胞中的纺锤体长度和滞后染色体频率。这些发现揭示了纺锤体力与桥联连接纠正之间的意外联系，并表明对纺锤体延伸力的药理学操纵可能用于降低癌细胞中的染色体不稳定性。
