The Mad1-Mad2 balancing act - a damaged spindle checkpoint in chromosome instability and cancer
The Mad1-Mad2 balancing act - a damaged spindle checkpoint in chromosome instability and cancer
复制标题
DOI：
10.1242/jcs.107037
复制
发表时间：
2012-09-15
影响因子：
4
通讯作者：
Kuan, Vivian Jen-Wei
中科院分区：
文献类型：
--
作者：
Schuyler, Scott C.;Wu, Yueh-Fu;Kuan, Vivian Jen-Wei
癌细胞通常是非整倍体。纺锤体检查点通过响应异常微管-动粒附着控制细胞周期进程来确保准确的染色体分离。对检查点的损伤，即检查点功能的部分丧失或获得，导致肿瘤发生期间的非整倍性。一种形式的损伤是检查点蛋白有丝分裂阻滞缺陷1和2（Mad 1和Mad 2）水平的变化，或Mad 1：Mad 2比例的变化。Mad 1和Mad 2水平的变化发生在人类癌症中，它们的表达受肿瘤抑制因子p53和视网膜母细胞瘤1（RB 1）的调节。通过采用标准测定，即在有丝分裂进入时添加有丝分裂毒物，已经表明检查点功能在许多癌细胞中是正常的。然而，在几个实验系统中，已经观察到该标准测定并不总是揭示由Mad 1或Mad 2的变化诱导的检查点畸变，其中相对于Mad 2过量的Mad 1可导致过早进入后期，并且过量的Mad 2可导致进入后期的延迟。这篇评论强调了Mad 1和Mad 2水平的变化如何导致纺锤体检查点受损，并探讨了这些变化如何导致染色体不稳定，从而导致肿瘤发生期间的非整倍体。
Cancer cells are commonly aneuploid. The spindle checkpoint ensures accurate chromosome segregation by controlling cell cycle progression in response to aberrant microtubule-kinetochore attachment. Damage to the checkpoint, which is a partial loss or gain of checkpoint function, leads to aneuploidy during tumorigenesis. One form of damage is a change in levels of the checkpoint proteins mitotic arrest deficient 1 and 2 (Mad1 and Mad2), or in the Mad1: Mad2 ratio. Changes in Mad1 and Mad2 levels occur in human cancers, where their expression is regulated by the tumor suppressors p53 and retinoblastoma 1 (RB1). By employing a standard assay, namely the addition of a mitotic poison at mitotic entry, it has been shown that checkpoint function is normal in many cancer cells. However, in several experimental systems, it has been observed that this standard assay does not always reveal checkpoint aberrations induced by changes in Mad1 or Mad2, where excess Mad1 relative to Mad2 can lead to premature anaphase entry, and excess Mad2 can lead to a delay in entering anaphase. This Commentary highlights how changes in the levels of Mad1 and Mad2 result in a damaged spindle checkpoint, and explores how these changes cause chromosome instability that can lead to aneuploidy during tumorigenesis.