Low Molecular Weight Cyclin E Overexpression Shortens Mitosis, Leading to Chromosome Missegregation and Centrosome Amplification
Low Molecular Weight Cyclin E Overexpression Shortens Mitosis, Leading to Chromosome Missegregation and Centrosome Amplification
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DOI：
10.1158/0008-5472.can-09-4094
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发表时间：
2010-06-15
期刊：
影响因子：
11.2
通讯作者：
Keyomarsi, Khandan
中科院分区：
文献类型：
--
作者：
Bagheri-Yarmand, Rozita;Biernacka, Anna;Keyomarsi, Khandan
细胞周期蛋白E的低分子量异构体（LMW-E）的过表达诱导染色体不稳定性;然而，这些肿瘤特异性形式导致基因组不稳定性的程度不同于全长细胞周期蛋白E（EL），并且潜在的机制尚未阐明。在这里，我们发现EL和LMW-E过表达损害G（2）-M转换不同，并导致不同程度的染色体不稳定性在乳腺癌模型系统。首先，最显著的区别是EL过表达使细胞周期停滞在前中期，而LMW-E过表达缩短有丝分裂的长度并加速有丝分裂的退出。其次，LMW-E过表达细胞是双核或多核的，具有扩增的中心体，而EL过表达细胞具有正常的中心体补体。第三，LMW-E过表达导致有丝分裂缺陷、中期染色体错误分离和后期桥，其中大部分在EL诱导时未检测到。LMW-E在正常和肿瘤细胞中诱导额外的有丝分裂缺陷与p53丢失。第四，LMW-E过表达细胞在诺考达唑存在下不能停滞。总的来说，LMW-E诱导介导的有丝分裂缺陷导致胞质分裂失败和多倍性，这表明LMW-E表达通过缩短有丝分裂长度来引发细胞染色体不稳定性。最后，LMW-E在人乳腺癌组织中的表达与中心体扩增和较高的核分级相关。这些结果表明，LMW-E过表达导致乳腺癌中中心体数量增加，这是基因组不稳定的先决条件。Cancer Res; 70（12）; 5074-84. (C)2010年AACR。
Overexpression of the low molecular weight isoforms (LMW-E) of cyclin E induces chromosome instability; however, the degree to which these tumor-specific forms cause genomic instability differs from that of full-length cyclin E (EL), and the underlying mechanism(s) has yet to be elucidated. Here, we show that EL and LMW-E overexpression impairs the G(2)-M transition differently and leads to different degrees of chromosome instability in a breast cancer model system. First, the most significant difference is that EL overexpression prolongs cell cycle arrest in prometaphase, whereas LMW-E overexpression reduces the length of mitosis and accelerates mitotic exit. Second, LMW-E-overexpressing cells are binucleated or multinucleated with amplified centrosomes, whereas EL-overexpressing cells have the normal complement of centrosomes. Third, LMW-E overexpression causes mitotic defects, chromosome missegregation during metaphase, and anaphase bridges during anaphase, most of which are not detected on EL induction. LMW-E induces additional mitotic defects in cooperation with p53 loss in both normal and tumor cells. Fourth, LMW-E-overexpressing cells fail to arrest in the presence of nocodazole. Collectively, the mitotic defects mediated by LMW-E induction led to failed cytokinesis and polyploidy, suggesting that LMW-E expression primes cells to accrue chromosomal instability by shortening the length of mitosis. Lastly, LMW-E expression in human breast cancer tissues correlates with centrosome amplification and higher nuclear grade. These results suggest that LMW-E overexpression leads to higher centrosome numbers in breast cancer, which is a prerequisite for genomic instability. Cancer Res; 70(12); 5074-84. (C) 2010 AACR.