Wong Jim, Fang Guowei
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
J Cell Biol. 2006 Jun 19;173(6):879-91. doi: 10.1083/jcb.200511132. Epub 2006 Jun 12.
Through a functional genomic screen for mitotic regulators, we identified hepatoma up-regulated protein (HURP) as a protein that is required for chromosome congression and alignment. In HURP-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in the activation of the spindle checkpoint. Although these defects transiently delayed mitotic progression, HeLa cells initiated anaphase without resolution of these deficiencies. This bypass of the checkpoint arrest provides a tumor-specific mechanism for chromosome missegregation and genomic instability. Mechanistically, HURP colocalized with the mitotic spindle in a concentration gradient increasing toward the chromosomes. HURP binds directly to microtubules in vitro and enhances their polymerization. In vivo, HURP stabilizes mitotic microtubules, promotes microtubule polymerization and bipolar spindle formation, and decreases the turnover rate of the mitotic spindle. Thus, HURP controls spindle stability and dynamics to achieve efficient kinetochore capture at prometaphase, timely chromosome congression to the metaphase plate, and proper interkinetochore tension for anaphase initiation.
通过对有丝分裂调节因子进行功能基因组筛选，我们鉴定出肝癌上调蛋白（HURP）是染色体汇聚和排列所必需的一种蛋白质。在HURP缺失的细胞中，未排列染色体的持续存在以及排列染色体上姐妹动粒间张力的降低导致纺锤体检查点激活。尽管这些缺陷暂时延迟了有丝分裂进程，但HeLa细胞在未解决这些缺陷的情况下就启动了后期。这种对检查点阻滞的绕过为染色体错分离和基因组不稳定提供了一种肿瘤特异性机制。从机制上讲，HURP与有丝分裂纺锤体共定位，其浓度梯度朝着染色体方向增加。HURP在体外直接与微管结合并增强其聚合作用。在体内，HURP稳定有丝分裂微管，促进微管聚合和双极纺锤体形成，并降低有丝分裂纺锤体的周转率。因此，HURP控制纺锤体的稳定性和动力学，以在前期实现有效的动粒捕获、使染色体及时汇聚到中期板，并为后期启动提供适当的动粒间张力。
