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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Surveillance mechanism linking Bub1 loss to the p53 pathway
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Surveillance mechanism linking Bub1 loss to the p53 pathway

机译：将Bub1丢失与p53途径联系起来的监测机制

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摘要

Bub1 is a kinase believed to function primarily in the mitotic spindle checkpoint. Mutation or aberrant Bub1 expression is associated with chromosomal instability, aneuploidy, and human cancer. We now find that targeting Bub1 by RNAi or simian virus 40 (SV40) large T antigen in normal human diploid fibroblasts results in premature senescence. Interestingly, cells undergoing replicative senescence were also low in Bub1 expression, although ectopic Bub1 expression in presenescent cells was insufficient to extend lifespan. Premature senescence caused by lower Bub1 levels depends on p53. Senescence induction was blocked by dominant negative p53 expression or depletion of p21~(CIP1), a p53 target. Importantly, cells with lower Bub1 levels and inactivated p53 became highly aneuploid. Taken together, our data highlight a role for p53 in monitoring Bub1 function, which may be part of a more general spindle checkpoint surveillance mechanism. Our data support the hypothesis that Bub1 compromise triggers p53-dependent senescence, which limits the production of aneuploid and potentially cancerous cells.
机译：Bub1是一种激酶，被认为主要在有丝分裂纺锤体检查点起作用。突变或异常Bub1表达与染色体不稳定，非整倍性和人类癌症有关。现在，我们发现在正常人二倍体成纤维细胞中，RNAi或猿猴病毒40（SV40）大T抗原靶向Bub1会导致早衰。有趣的是，尽管复制前衰老细胞中的异位Bub1表达不足以延长其寿命，但经历复制衰老的细胞的Bub1表达也较低。较低的Bub1水平引起的过早衰老取决于p53。显性负性p53表达或p21〜（CIP1）（p53靶标）的耗尽可阻止衰老诱导。重要的是，具有较低Bub1水平和p53失活的细胞成为高度非整倍体。综上所述，我们的数据强调了p53在监测Bub1功能中的作用，这可能是更通用的主轴检查点监视机制的一部分。我们的数据支持Bub1损害触发p53依赖性衰老的假说，这限制了非整倍体和潜在癌细胞的产生。

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