Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1
Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1
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DOI：
10.1073/pnas.0600447103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Chen, Li
中科院分区：
文献类型：
--
作者：
Vassilev, Lyubomir T.;Tovar, Christian;Chen, Li
CDK 1是一种非冗余的细胞周期蛋白依赖性激酶（CDK），在有丝分裂中起重要作用，但其多种功能在分子水平上仍知之甚少。在这里，我们确定了一种选择性的小分子CDK 1抑制剂，可逆地阻止人类细胞在细胞周期的G（2）/M边界，并允许在早期有丝分裂有效的细胞同步化。在细胞分裂过程中抑制CDK 1表明，其活性对于维持细胞的有丝分裂状态、防止复制起点许可和过早胞质分裂是必要且足够的。虽然CDK 1抑制长达24小时耐受性良好，但更长时间暴露于抑制剂会诱导肿瘤细胞凋亡，这表明选择性CDK 1抑制剂可能在癌症治疗中具有实用性。
CDK1 is a nonredundant cyclin-dependent kinase (CDK) with an essential role in mitosis, but its multiple functions still are poorly understood at a molecular level. Here we identify a selective small-molecule inhibitor of CDK1 that reversibly arrests human cells at the G(2)/M border of the cell cycle and allows for effective cell synchronization in early mitosis. Inhibition of CDK1 during cell division revealed that its activity is necessary and sufficient for maintaining the mitotic state of the cells, preventing replication origin licensing and premature cytokinesis. Although CDK1 inhibition for up to 24 h is well tolerated, longer exposure to the inhibitor induces apoptosis in tumor cells, suggesting that selective CDK1 inhibitors may have utility in cancer therapy.