Zachos George, Black Elizabeth J, Walker Mark, Scott Mary T, Vagnarelli Paola, Earnshaw William C, Gillespie David A F
Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom.
Dev Cell. 2007 Feb;12(2):247-60. doi: 10.1016/j.devcel.2007.01.003.
The spindle checkpoint delays anaphase onset in cells with mitotic spindle defects. Here, we show that Chk1, a component of the DNA damage and replication checkpoints, protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol, but not when microtubules are completely depolymerized by nocodazole. Spindle checkpoint failure in Chk1-deficient cells correlates with decreased Aurora-B kinase activity and impaired phosphorylation and kinetochore localization of BubR1. Furthermore, Chk1 phosphorylates Aurora-B and enhances its catalytic activity in vitro. We propose that Chk1 augments spindle checkpoint signaling and is required for optimal regulation of Aurora-B and BubR1 when kinetochores produce a weakened signal. In addition, Chk1-deficient cells exhibit increased resistance to taxol. These results suggest a mechanism through which Chk1 could protect against tumorigenesis through its role in spindle checkpoint signaling.
纺锤体检查点会延迟有丝分裂纺锤体缺陷细胞进入后期。在此，我们表明，DNA损伤和复制检查点的组成部分Chk1可保护脊椎动物细胞免受自发染色体错分离的影响，并且当纺锤体功能被紫杉醇破坏时，维持后期延迟需要Chk1，但当微管被诺考达唑完全解聚时则不需要。Chk1缺陷细胞中的纺锤体检查点失败与Aurora - B激酶活性降低以及BubR1的磷酸化和动粒定位受损相关。此外，Chk1在体外使Aurora - B磷酸化并增强其催化活性。我们提出，当动粒产生减弱的信号时，Chk1增强纺锤体检查点信号传导，并且是Aurora - B和BubR1最佳调节所必需的。此外，Chk1缺陷细胞对紫杉醇的抗性增加。这些结果提示了一种机制，通过该机制Chk1可通过其在纺锤体检查点信号传导中的作用预防肿瘤发生。
