How does the spindle checkpoint convert Cdc20 into an APC/C substrate?

至关重要的是，细胞分裂应该产生两个完全相同的子细胞。子代细胞从原始细胞获得遗传物质的精确副本。在细胞分裂过程中，细胞仔细监测染色体形式的遗传物质的分布。监控此过程的系统称为主轴组件检查点。如果主轴组件检查点工作不正常，子代细胞将无法获得遗传物质的精确副本。这导致传递给两个女儿的染色体数量不相等，这被称为非整倍体。最近的研究表明，非整倍体可以启动肿瘤的形成，事实上，许多肿瘤细胞系似乎有一个微弱的纺锤体组装检查点。我们正集中精力试图了解纺锤体装配检查点在正常细胞中的功能，并深入了解它在肿瘤中可能变得有缺陷的原因。我们知道主轴装配检查点抑制蛋白CDC20。CDC20是一个被称为后期促进复合体/环体(APC/C)的大型复合体的激活剂，负责在有丝分裂中降解特定的蛋白质。主轴组装检查点的两个组件，即MAD2和BubR1直接与CDC20结合，并负责这种抑制。我们最近发现，主轴组件检查点不仅抑制CDC20，而且它还通过APC/C针对CDC20进行降解。这意味着当主轴组件检查点激活时，CDC20从APC/C的激活剂切换到衬底。我们还表明，CDC20的这种退化对于维持一个活跃的检查点是重要的。现在我们想了解主轴组件检查点如何将CDC20转变为APC/C的底物，我们特别关注BubR1在这方面的作用，因为这似乎是负责这一点的关键组件。对于BubR1来说，要想以Cdc20为目标进行降解，它需要能够与Cdc20结合。我们已经发现MAD2对于BubR1与Cdc20的结合是绝对必要的，我们将调查为什么会这样。

It is crucial that cell division should generate two identical daughter cells. The daughter cells recieve an exact copy of the genetic material from the original cell. The distribution of the genetic material in the form of chromosomes is monitored carefully by the cell during cell division. The system monitoring this process is referred to as the Spindle Assembly Checkpoint. If the Spindle Assembly Checkpoint is not working properly the daughter cells will not get an exact copy of the genetic material. This results in an unequal number of chromosomes being passed to the two daughters and this is called called aneuploidy. Recent research indicates that aneuploidy can initiate tumor formation and indeed many tumor cell lines appear to have a weak Spindle Assembly Checkpoint. We are focusing our efforts on trying to understand how the Spindle Assembly Checkpoint functions in normal cells, and to gain insight into why it might become defective in tumors. We know the Spindle Assembly Checkpoint inhibits the protein Cdc20. Cdc20 is an activator of a large complex called the Anaphase Promoting Complex/Cyclosome (APC/C) that is responsible for degrading specific proteins in mitosis. Two components of the Spindle Assembly Checkpoint namely Mad2 and BubR1 bind directly to Cdc20 and are responsible for this inhibition. We have recently found that not only does the Spindle Assembly Checkpoint inhibit Cdc20 but it also targets Cdc20 for degradation via APC/C. This means that when the Spindle Assembly Checkpoint is active Cdc20 switches from an activator of the APC/C to a substrate. We have also shown that this degradation of Cdc20 is important for maintaining an active checkpoint. We now want to understand how the Spindle Assembly Checkpoint turns Cdc20 into a substrate of the APC/C and we are particular focusing on the role of BubR1 in this aspect since this appear to be the key component responsible for this. For BubR1 to target Cdc20 for degradation it needs to be able to bind to Cdc20. We have found that Mad2 is absolutely essential for the binding of BubR1 to Cdc20 and we will investigate why this is so.