Centrosome separation; a careful balancing act.
Centrosome separation; a careful balancing act.
复制标题
中心体分离；
DOI：
10.1080/15384101.2015.1080981
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Whalley HJ
中科院分区：
文献类型：
--
作者：
Whalley HJ
在哺乳动物细胞有丝分裂过程中，中心体分离对于双极纺锤体的形成和随后染色体的精确分离至关重要。调节这一重要过程的多种机制仍在阐明中，在前期核膜破裂（NEBD）之前和前中期的NEBD之后，有不同的途径起作用。这些机制包括皮层肌动蛋白动力学，多个分子马达和微管（MT）从动粒推力。然而，正末端导向驱动蛋白Eg 5是迄今为止确定的最重要的参与者。Eg 5的MT滑动活性对于许多物种的前中期中心体分离是必不可少的，1并且在哺乳动物细胞中较少了解的前期途径中也起作用。2用Eg 5抑制剂处理细胞导致单极纺锤体和有丝分裂停滞，3这在过去几年中引起了人们对这些药物作为潜在抗癌疗法的极大兴趣。在我们努力理解中心体分离的复杂调控过程中，很明显，反对分离的力量对于实现有效染色体比对所需的正确力量平衡也很重要。2，4已知在NEBD后产生这些力的蛋白质包括负端定向驱动蛋白HSET和动力蛋白，其消耗使得细胞在Eg 5抑制下更容易形成双极纺锤体。最近，我们确定了鸟嘌呤核苷酸交换因子（GEF）Tiam 1和其底物Rac作为第一个模块，以抵消Eg 5驱动的中心体分离的前期。2 Tiam 1-Rac信号通路在细胞间粘附、迁移和存活中起重要作用。我们发现Tiam 1和Rac也定位于有丝分裂的中心体，并产生一种向内的力，这对有效的染色体对齐至关重要。2我们很想了解更多关于这种新的有丝分裂作用的机制，最近我们有了两个重要的相关发现。第一个发现来自于一个简单的观察，即有丝分裂停滞后，免疫印迹上Tiam 1的迁移率发生了变化。由此，我们确定了一个Cdk 1磷酸化位点，S1466，这是必不可少的Tiam 1拮抗Eg 5在有丝分裂。5这很有趣，因为有丝分裂的主要调节因子Cdk 1此前仅被描述为积极调节中心体分离。CDK1
Centrosome separation is critical for formation of a bipolar spindle and the subsequent accurate segregation of chromosomes during mammalian cell mitosis. The multiple mechanisms that regulate this important process are still being elucidated, with separate pathways acting before nuclear envelope breakdown (NEBD) in prophase and post-NEBD in prometaphase. These mechanisms include cortical actin dynamics, multiple molecular motors and microtubule (MT) pushing forces from kinetochores. However, the plus-end-directed kinesin Eg5 is irrefutably the most important player identified so far. The MT-sliding activity of Eg5 is essential for centrosome separation in prometaphase across many species, 1 and also plays a role in the less-understood prophase pathway in mammalian cells. 2 Treatment of cells with Eg5 inhibitors leads to monopolar spindles and mitotic arrest, 3 which has led to much interest in these drugs as potential anti-cancer therapies over the last few years. In our efforts to understand the complex regulation of centrosome separation, it has become apparent that forces that oppose separation are also important to achieve the correct balance of forces required for efficient chromosome alignment. 2, 4 Proteins known to generate these forces after NEBD include the minus-end directed kinesins HSET and dynein, whose depletion allows cells to more easily form bipolar spindles under Eg5 inhibition. More recently, we identified the guanine-nucleotide exchange factor (GEF) Tiam1 and its substrate Rac as the first module to counteract Eg5-driven centrosome separation in prophase. 2 Tiam1-Rac signaling was previously known for its regulation of cell-cell adhesion, migration and survival. We found that Tiam1 and Rac also localize to the centrosomes in mitosis, and create an inward force that is essential for efficient chromosome alignment. 2 Intrigued to learn more about the mechanisms of this novel mitotic role, we have recently made 2 important and related findings. 5The first finding arose from a simple observation of a shift in the mobility of Tiam1 on immunoblots following mitotic arrest. From this we identified a Cdk1 phosphorylation site, S1466, which is essential for Tiam1 to antagonise Eg5 in mitosis. 5 This is intriguing, since Cdk1, the master regulator of mitosis, has previously been described only to positively regulate centrosome separation. Cdk1