有丝分裂前期检查点Chfr基因作用的研究进展

Advance of Study on Effects of Chfr Gene of Mitosis Prophase Checkpoint——Review

细胞在长期进化过程中发展出了一套保证细胞周期中DNA复制和染色体分配质量的检查机制 ,通常被称为细胞周期检查点 (checkpoint)。有丝分裂前期检查点Chfr(checkpointwithFHAandringfinger)蛋白在正常组织中广泛表达 ,其结构和功能都十分保守 ,许多研究表明Chfr在细胞分裂过程中发挥着重要作用 ,细胞分裂存在有丝分裂应激时 ,Chfr通路激活引起Plk1的泛素化并降解 ,控制Cdc2激酶的活性 ,延迟染色体凝集和中心体分离 ,阻止细胞于有丝分裂前期 ,它的表达增强细胞对应激的生存能力。本文对Chfr基因的结构 ,Chfr蛋白质的作用和功能研究进展作一综述。

Chfr, a mitotic stress checkpoint gene, regulates a prophase delay in cells exposed to agents that disrupt microtubules, such as nocodazole and taxol. Chfr expression was ubiquitious in normal human tissues. It is very high conserved between human and mice. Preliminary sutdies indicated that Chfr expression was cell cycle regulated and it dependent on its ubiqitin ligase activity. The direct target of the Chfr pathway was Polo like kinase 1 (Plk1). Ubiquitination of Plk1 by Chfr delayed the activation of the Cdc25C phosphatase and the inactivation of the Weel kinase, leading to a delay in Cdc 2 activation. The chfr gene was inactivated owing to lack of expression or by mutation in some human cancer cell lines examined. Normal primary cells and tumour cell lines that express wild type chfr exhibited delayed entry into metaphase when centrosome separation was inhibited by mitotic stress. In contrast, the tumour cell lines that had lost chfr function entered metaphase without delay. Ecotopic expression of wild type chfr restored the cell cycle delay and increased the ability of the cells to survive mitotic stress. Thus, chfr defines a checkpoint that delays entry into metaphase in response to mitotic stress. The progress of research on structure of Chfr gene and effects of Chfr protein was reviewed.