有丝分裂检验点基因BubR1的研究进展

BubR1是存在于哺乳动物中的有丝分裂检查点基因家族Mad3的同源基因,其编码蛋白BubR1是一个多结构域蛋白,在监测细胞有丝分裂前中期向后期转化的过程中扮演重要的角色。BubR1可以通过自身或作为MCC的成分抑制APC的活性,从APC隔离Cdc20或者通过连接到微管驱动蛋白cENP—E,激活有丝分裂检查点信号级联放大。近年来关于BubR1的结构、功能及作用机理等研究工作颇为引人关注。这些研究表明:人BUBR11基因定位于人类染色体15q14-21,其编码蛋白BubR1在整个有丝分裂中聚集在外层动粒板;BubR1缺陷导致对DNA损伤的妥协反应,它的完全切除导致大量细胞凋亡甚至胚胎致死;BubR1单基因剔除可增强剔除基因组不稳定性,并导致肿瘤发生;BubR1表达减少至10%的导致一系列早老相关的表型出现;BubR1 /-Apcmin/ 复合突变提示BubR1和Apc相互作用调节中期一后期转化,这一反常现象可能在结直肠癌的基因组稳定性、发生和进展中发挥作用。本文将对BubR1蛋白就以上内容做一综述。

The Latest Progress in Studies of Mitotic Checkpoint Gene BubR1

The mammalian BubR1 gene is a homologue of the mitotic checkpoint gene Mad3 in budding yeast.Its gene product BubR1 is a multi-domain protein.BubR1 play an important role in monitoring the progression from prometaphase to anaphase in mitosis.BubR1 can inhibit the activity of APC,either by itself or as a component of the MGC,by sequestering Cdc20 from the APC.BubR1 activates mitotic checkpoint signaling cascades,by binding to the microtubule motor protein CENP-E.The human BUBR1 gene,located on human chromosome 15q14-21,has been shown to be concentrated in the outer kinetochore plate throughout mitosis.BubR1 deficiency leads to a compromised response to DNA damage.BUBR1-/-embryos fail to survive be- yond day 8.5 in utero as a result of extensive apoptosis.Mutant mice with low levels of BubR1 develop progressive anenploidy a- long with a variety of aging-associated features.BubR1 /-ApcMin/ compound mutant mice develop 10 times more colonic tu- mors than ApcMin/ mice suggests that BubR1 and Apc functionally interact in regulating metaphase anaphase transition,deregula- tion of which may play a key role in genomic instability and development and progression of colorectal cancer.The present article reviews the latest progress in the studies of BubR1 in terms of its molecular structure,biological functions,gene structure,and its association with tumorigenesis and senescence.Results of the studies using BubR1 knock out mice were also discussed.