Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability
Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability
复制标题
Cdk1 磷酸化 CUEDC2 促进纺锤体检查点失活和染色体不稳定
DOI：
10.1038/ncb2287
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发表时间：
2011-08-01
影响因子：
21.3
通讯作者：
Zhang, Xue-Min
中科院分区：
文献类型：
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作者：
Gao, Yan-Fei;Li, Teng;Zhang, Xue-Min
非整倍体和染色体不稳定是人类癌症的主要特征。这些异常可能是纺锤体组装检查点(SAC)的缺陷造成的，SAC是通过限制后期促进复合体/环体(APC/C)的活性来监测染色体准确分离的机制。在这里，我们证明了含有线索结构域的蛋白CUEDC2是一种细胞周期调节因子，它促进纺锤体检查点失活并释放APC/C从检查点抑制中释放出来。CUEDC2在有丝分裂过程中被CDK1磷酸化。CUEDC2的耗尽会导致中期-后期转换的检查点相关延迟。磷酸化的CUEDC2与APC/C的激活剂CDC20结合，促进MAD2从APC/C-CDC20释放，进而激活APC/C。CUEDC2过表达导致APC/C提前激活，导致染色体错误分离和非整倍体。有趣的是，CUEDC2在许多类型的肿瘤中高度表达。这些结果表明，CUEDC2是有丝分裂进程的关键调节因子，CUEDC2的失调可能通过导致染色体不稳定而促进肿瘤的发展。
Aneuploidy and chromosomal instability are major characteristics of human cancer. These abnormalities can result from defects in the spindle assembly checkpoint (SAC), which is a surveillance mechanism for accurate chromosome segregation through restraint of the activity of the anaphase-promoting complex/cyclosome (APC/C). Here, we show that a CUE-domain-containing protein, CUEDC2, is a cell-cycle regulator that promotes spindle checkpoint inactivation and releases APC/C from checkpoint inhibition. CUEDC2 is phosphorylated by Cdk1 during mitosis. Depletion of CUEDC2 causes a checkpoint-dependent delay of the metaphase–anaphase transition. Phosphorylated CUEDC2 binds to Cdc20, an activator of APC/C, and promotes the release of Mad2 from APC/C–Cdc20 and subsequent APC/C activation. CUEDC2 overexpression causes earlier activation of APC/C, leading to chromosome missegregation and aneuploidy. Interestingly, CUEDC2 is highly expressed in many types of tumours. These results suggest that CUEDC2 is a key regulator of mitosis progression, and that CUEDC2 dysregulation might contribute to tumour development by causing chromosomal instability.