Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.
Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.
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DOI：
10.1083/jcb.200706015
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发表时间：
2007-10-22
期刊：
影响因子：
--
通讯作者：
van Deursen JM
中科院分区：
文献类型：
--
作者：
Jeganathan K;Malureanu L;Baker DJ;Abraham SC;van Deursen JM
有丝分裂检查点蛋白Bub1的生理作用是未知的。为了研究这一作用，我们产生了一系列突变小鼠的梯度降低Bub1表达使用野生型，亚纯型，和敲除等位基因。尽管有丝分裂检查点活性减弱且非整倍体细胞百分比高，但Bub1亚纯型小鼠是可行的、可生育的且明显正常。Bub1单倍体不足的小鼠，其Bub1蛋白的减少比Bub1亚纯型小鼠轻微，也表现出检查点活性降低和非整倍体增加，但程度较轻。虽然来自Bub1亚纯型和单倍体不足小鼠的细胞具有相似的染色体错误分离率，但异常分离后的细胞死亡随着Bub1水平的下降而显著降低。重要的是，Bub1亚型小鼠对自发性肿瘤高度敏感，而Bub1单倍型不足小鼠则不然。这些研究结果表明，低于临界阈值的Bub1的损失驱动自发性肿瘤发生，并表明，除了确保适当的染色体分离，Bub1是重要的染色体错误分离时介导的细胞死亡。
The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate.
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影响因子：
64.8
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
DOI：
10.1073/pnas.0401142101
发表时间：
2004-06-08
影响因子：
11.1
作者：
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作者：
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