Mps1 as a link between centrosomes and genomic instability.
Mps1 as a link between centrosomes and genomic instability.
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MPS1作为中心体与基因组不稳定性之间的联系。
DOI：
10.1002/em.20476
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发表时间：
2009-10
影响因子：
2.8
通讯作者：
Fisk, Harold A.
中科院分区：
文献类型：
--
作者：
Kasbek, Christopher;Yang, Ching-Hui;Fisk, Harold A.
中心体是微管组织中心，在有丝分裂前必须精确复制。中心体调节有丝分裂纺锤体的组装，而过多的中心体的存在会导致异常有丝分裂纺锤体的产生，从而产生染色体分离错误。许多人类肿瘤具有过多的中心体，导致原位产生异常的纺锤体。在一些肿瘤中，这些额外的中心体出现在非整倍体之前，这表明中心体复制的缺陷可能会促进基因组的不稳定和肿瘤的发生。中心体复制需要MPS1蛋白激酶，阻止中心体对MPS1蛋白酶体的依赖降解会增加其局部浓度，并导致在延长的S时相中产生过剩的中心体。在这里，我们证明了MPS1的降解在两个肿瘤来源的细胞系中被错误地调节，并且未能适当地降解MPS1与这些细胞在延长的S期产生额外中心体的能力有关。在21NT乳腺肿瘤来源的细胞系中，通常被结构性降解的突变Mps1蛋白可以在中心体积累并扰乱中心体复制，这表明这些细胞在将Mps1靶向蛋白酶体的机制上存在缺陷。相反，U2OS骨肉瘤细胞系表达一种不可降解的Mps1形式，我们发现即使在非常低的表达水平下，这也会导致中心粒过度复制的剂量依赖关系。我们的数据表明，Mps1降解中的缺陷可以通过多种机制发生，并表明Mps1可能在中心体复制的控制和基因组不稳定性之间提供了联系。
Centrosomes are microtubule-organizing centers that must be precisely duplicated prior to mitosis. Centrosomes regulate mitotic spindle assembly, and the presence of excess centrosomes leads to the production of aberrant mitotic spindles that generate chromosome segregation errors. Many human tumors possess excess centrosomes that lead to the production of abnormal spindles in situ. In some tumors these extra centrosomes appear before aneuploidy, suggesting that defects in centrosome duplication might promote genomic instability and tumorigenesis. The Mps1 protein kinase is required for centrosome duplication, and preventing the proteasome-dependent degradation of Mps1 at centrosomes increases its local concentration and causes the production of excess centrosomes during a prolonged S-phase. Here we show that Mps1 degradation is misregulated in two tumor-derived cell lines, and that the failure to appropriately degrade Mps1 correlates with the ability of these cells to produce extra centrosomes during a prolonged S-phase. In the 21NT breast-tumor derived cell line a mutant Mps1 protein that is normally constitutively degraded can accumulate at centrosomes and perturb centrosome duplication, suggesting that these cells have a defect in the mechanisms that target Mps1 to the proteasome. In contrast, the U2OS osteosarcoma cell line expresses a non-degradable form of Mps1, which we show causes the dose-dependent over duplication of centrioles even at very low levels of expression. Our data demonstrate that defects in Mps1 degradation can occur through multiple mechanisms, and suggest that Mps1 may provide a link between the control of centrosome duplication and genomic instability.
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DOI：
10.1073/pnas.95.6.2950
发表时间：
1998-03-17
影响因子：
11.1
作者：
Lingle, WL;Lutz, WH;Salisbury, JL
通讯作者：
Salisbury, JL
影响因子：
11.8
作者：
Kleylein-Sohn, Julia;Westendorf, Jens;Nigg, Erich A.
通讯作者：
Nigg, Erich A.
影响因子：
3.3
作者：
Liu, ST;Chan, GKT;Yen, TJ
通讯作者：
Yen, TJ
影响因子：
3.3
作者：
Guarguaglini, G;Duncan, PI;Nigg, EA
通讯作者：
Nigg, EA
DOI：
10.1073/pnas.032479999
发表时间：
2002-02-19
影响因子：
11.1
作者：
Lingle, WL;Barrett, SL;Salisbury, JL
通讯作者：
Salisbury, JL