Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1
Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1
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DOI：
10.1128/mcb.25.10.4046-4061.2005
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发表时间：
2005-05-01
影响因子：
5.3
通讯作者：
Fukasawa, K
中科院分区：
文献类型：
--
作者：
Oikawa, T;Okuda, M;Fukasawa, K
消除中心体数字稳态的调节机制（如在缺乏 p53 的细胞中所见）会导致中心体异常扩增，从而增加染色体分离错误的频率，从而导致癌细胞中经常观察到的染色体不稳定。我们之前曾报道过，p53（-/-）小鼠细胞在长期培养中会经历与肿瘤进展过程中观察到的类似的基因组趋同；早期传代的p53(-/-)细胞由于与中心体扩增相关的广泛染色体不稳定而具有核型异质性，而晚期传代的p53(-/-)细胞是非整倍体，但核型均质且染色体稳定。此外，它们含有数量正常的中心体。通过对早期和晚期传代p53(-/-)细胞的微阵列分析，我们鉴定了BubR1纺锤体检查点蛋白，该蛋白在晚期传代p53(-/-)细胞中抑制中心体扩增和稳定染色体方面发挥着关键作用。 BubR1 的上调增强了检查点功能，可有效感知与中心体扩增相关的纺锤体/染色体畸变。我们进一步发现BubR1转录很大程度上受p53控制。在早期传代的p53(-/-)细胞中，BubR1表达较低，并且响应微管毒素的检查点功能显着受损。然而，在传代后期的细胞中，BubR1 表达的重新恢复可以恢复微管毒素引起的有丝分裂畸变的检查点功能。我们的研究证明了培养细胞中基因组趋同的分子方面，为理解肿瘤的逐步进展提供了关键信息。
Elimination of the regulatory mechanism underlying numeral homeostasis of centrosomes, as seen in cells lacking p53, results in abnormal amplification of centrosomes, which increases the frequency of chromosome segregation errors, and thus contributes to the chromosome instability frequently observed in cancer cells. We have previously reported that p53(-/-) mouse cells in prolonged culture undergo genomic convergence similar to that observed during tumor progression; early-passage p53(-/-) cells are karyotypically heterogeneous due to extensive chromosome instability associated with centrosome amplification, while late-passage p53(-/-) cells are aneuploid yet karyotypically homogeneous and chromosomally stable. Moreover, they contain numerically normal centrosomes. Through the microarray analysis of early- and late-passage p53(-/-) cells, we identified the BubR1 spindle checkpoint protein, which plays a critical role in suppression of centrosome amplification and stabilization of chromosomes in late-passage p53(-/-) cells. Up-regulation of BubR1 augments the checkpoint function, which effectively senses the spindle/chromosome aberrations associated with centrosome amplification. We further found that BubR1 transcription is largely controlled by p53. In early-passage p53(-/-) cells, BubR1 expression is low and the checkpoint function in response to microtubulle toxin is considerably compromised. In late-passage cells, however, regaining of BubR1 expression restores the checkpoint function to mitotic aberrations caused by microtubulle toxin. Our studies demonstrate the molecular aspect of genomic convergence in cultured cells, providing critical information for understanding the stepwise progression of tumors.