Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Abramson Family Cancer Research Institute, 252 John Morgan Building, 3600 Hamilton Walk, Philadelphia, PA 19104, USA.
Exp Mol Pathol. 2010 Apr;88(2):225-33. doi: 10.1016/j.yexmp.2009.12.004. Epub 2009 Dec 23.
In mitosis, the duplicated chromosomes are separated and equally distributed to progeny cells under the guidance of the spindle, a dynamic microtubule network. Previous studies revealed a mitotic checkpoint that prevents segregation of the chromosomes until all of the chromosomes are properly attached to microtubules through the kinetochores. A variety of kinetochore-localized proteins, including Mad2 and Cdc20, have been implicated in controlling the mitotic checkpoint. Here we report that both Mad2 and Cdc20 can physically associate with Nek2, a serine/threonine kinase implicated in centrosome functions. We show that, similar to Nek2, the endogenous Cdc20 protein can be detected in the centrosome and the spindle poles. Both Cdc20 and Mad2 can be phosphorylated by Nek2. Moreover, our studies demonstrate that overexpression of Nek2 enhances the ability of Mad2 to induce a delay in mitosis. These observations indicate that Nek2 may act upon the Mad2-Cdc20 protein complex and play a critical role in regulating the mitotic checkpoint protein complex. We propose that overexpression of Nek2 may promote aneuploidy by disrupting the control of the mitotic checkpoint.
在有丝分裂过程中，在纺锤体的指导下，复制的染色体被分离并均等分配到子细胞中，纺锤体是一个动态的微管网络。以前的研究揭示了一个有丝分裂检查点，该检查点可以防止染色体分离，直到所有的染色体都通过动粒正确地附着到微管上。多种动粒定位蛋白，包括 Mad2 和 Cdc20，已被认为参与控制有丝分裂检查点。在这里，我们报告说 Mad2 和 Cdc20 都可以与 Nek2 物理结合，Nek2 是一种丝氨酸/苏氨酸激酶，参与中心体功能。我们表明，类似于 Nek2，内源性 Cdc20 蛋白可以在中心体和纺锤体极检测到。Cdc20 和 Mad2 都可以被 Nek2 磷酸化。此外，我们的研究表明，Nek2 的过表达增强了 Mad2 诱导有丝分裂延迟的能力。这些观察结果表明，Nek2 可能作用于 Mad2-Cdc20 蛋白复合物，并在调节有丝分裂检查点蛋白复合物中发挥关键作用。我们提出，Nek2 的过表达可能通过破坏有丝分裂检查点的控制而导致非整倍体。
