Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells.
Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells.
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DOI：
10.1371/journal.pone.0006564
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发表时间：
2009-08-10
期刊：
影响因子：
3.7
通讯作者：
Cimini D
中科院分区：
文献类型：
--
作者：
Silkworth WT;Nardi IK;Scholl LM;Cimini D
许多癌细胞表现出一种CIN（染色体不稳定）表型，通过这种表型，它们在每个细胞周期中表现出高比率的染色体丢失或获得。多年来，许多不同的机制，包括有丝分裂纺锤体多极性、细胞分裂失败和分裂着丝点定向，已被提出作为CIN的原因。然而，一个全面的理论是如何延续CIN仍然缺乏。我们使用CIN结肠直肠癌细胞作为模型系统来研究CIN可能的细胞机制。我们发现CIN细胞在有丝分裂早期经常组装多极纺锤体。然而，多极后期细胞非常罕见，活细胞实验表明几乎所有CIN细胞都以双极方式分裂。此外，固定细胞分析显示，在双极晚期CIN细胞中，端粒附着的滞后染色体频率较高，而在多极前期与双极前期相比，端粒附着的频率更高。最后，我们发现多极CIN前期通常在所有纺锤极都具有γ-微管蛋白，并且相当一部分双极中期/早期晚期CIN细胞在单个纺锤极具有多个中心体。综上所述，我们的数据提出了一个模型，通过该模型可以很容易地在多极前期建立分裂着丝点附着物。这些多极前期细胞在后期开始前大部分会发生双极化，并且由于后期滞后染色体的存在，残余的分裂附著体会产生染色体错误分离。我们认为这种纺锤杆合并机制是导致癌细胞染色体不稳定的主要因素。
Many cancer cells display a CIN (Chromosome Instability) phenotype, by which they exhibit high rates of chromosome loss or gain at each cell cycle. Over the years, a number of different mechanisms, including mitotic spindle multipolarity, cytokinesis failure, and merotelic kinetochore orientation, have been proposed as causes of CIN. However, a comprehensive theory of how CIN is perpetuated is still lacking. We used CIN colorectal cancer cells as a model system to investigate the possible cellular mechanism(s) underlying CIN. We found that CIN cells frequently assembled multipolar spindles in early mitosis. However, multipolar anaphase cells were very rare, and live-cell experiments showed that almost all CIN cells divided in a bipolar fashion. Moreover, fixed-cell analysis showed high frequencies of merotelically attached lagging chromosomes in bipolar anaphase CIN cells, and higher frequencies of merotelic attachments in multipolar vs. bipolar prometaphases. Finally, we found that multipolar CIN prometaphases typically possessed γ-tubulin at all spindle poles, and that a significant fraction of bipolar metaphase/early anaphase CIN cells possessed more than one centrosome at a single spindle pole. Taken together, our data suggest a model by which merotelic kinetochore attachments can easily be established in multipolar prometaphases. Most of these multipolar prometaphase cells would then bi-polarize before anaphase onset, and the residual merotelic attachments would produce chromosome mis-segregation due to anaphase lagging chromosomes. We propose this spindle pole coalescence mechanism as a major contributor to chromosome instability in cancer cells.
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影响因子：
21.3
作者：
Bakhoum, Samuel F.;Thompson, Sarah L.;Manning, Amity L.;Compton, Duane A.
通讯作者：
Compton, Duane A.
影响因子：
4
作者：
Cimini, D;Moree, B;Salmon, ED
通讯作者：
Salmon, ED
影响因子：
64.8
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
4.3
作者：
Cimini, Daniela
通讯作者：
Cimini, Daniela
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