Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression
Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression
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DOI：
10.1158/0008-5472.can-03-3908
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Fukasawa, K
中科院分区：
文献类型：
--
作者：
Kawamura, K;Izumi, H;Fukasawa, K
中心体扩增在人类癌症中经常发生，是染色体不稳定(CIN)的主要原因。在小鼠细胞中，中心体扩增很容易被P53的缺失或突变失活所诱导。然而，在人类细胞中，单独沉默内源性p53并不能诱导中心体扩增或CIN，尽管在人类癌症中可以检测到P53突变和CIN/中心体扩增之间的高度相关性，这表明人类细胞中存在额外的调节机制(S)，以确保中心体的数字完整性和基因组的完整性。细胞周期蛋白E是CDK2的一个调节亚基，在中心体复制中起关键作用，在人类癌症中经常过度表达。我们发现，细胞周期蛋白E的过表达与p53的缺失一起有效地诱导了人膀胱癌细胞中心体的扩增和CIN，但不是通过细胞周期蛋白E的过表达或p53的单独缺失来实现的。我们将这些发现推广到膀胱癌标本中，发现中心体扩增与细胞周期蛋白E过度表达和p53失活同时发生密切相关，但与细胞周期蛋白E过度表达或p53失活无关。由于与小鼠细胞相比，人类细胞中细胞周期蛋白E的表达受到严格控制，我们的发现表明，这种对细胞周期蛋白E表达的严格调控在人类细胞中心体的数字动态平衡中起着额外的作用，而细胞周期蛋白E表达的解除调控，以及p53的失活，导致中心体放大。
Centrosome amplification frequently occurs in human cancers and is a major cause of chromosome instability (CIN). In mouse cells, centrosome amplification can be readily induced by loss or mutational inactivation of p53. In human cells, however, silencing of endogenous p53 alone does not induce centrosome amplification or CIN, although high degrees of correlation between p53 mutation and CIN/centrosome amplification in human cancer can be detected, suggesting the presence of additional regulatory mechanism(s) in human cells that ensures the numeral integrity of centrosomes and genomic integrity. Cyclin E, a regulatory subunit for CDK2 that plays a key role in centrosome duplication, frequently is over-expressed in human cancers. We found that cyclin E overexpression, together with loss of p53, efficiently induces centrosome amplification and CIN in human bladder cancer cells but not by either cyclin E overexpression or loss of p53 alone. We extended these findings to bladder cancer specimens and found that centrosome amplification is strongly correlated with concomitant occurrence of cyclin E overexpression and p53 inactivation but not with either cyclin E overexpression or p53 inactivation alone. Because cyclin E expression is strictly controlled in human cells compared with mouse cells, our findings suggest that this stringent regulation of cyclin E expression plays an additional role underlying numeral homeostasis of centrosomes in human cells and that deregulation of cyclin E expression, together with inactivation of p53, results in centrosome amplification.