Duensing A, Liu Y, Perdreau S A, Kleylein-Sohn J, Nigg E A, Duensing S
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Oncogene. 2007 Sep 20;26(43):6280-8. doi: 10.1038/sj.onc.1210456. Epub 2007 Apr 16.
Abnormal centrosome numbers are detected in virtually all cancers. The molecular mechanisms that underlie centrosome amplification, however, are poorly characterized. Based on the model that each maternal centriole serves as a template for the formation of one and only one daughter centriole per cell division cycle, the prevailing view is that centriole overduplication arises from successive rounds of centriole reproduction. Here, we provide evidence that a single maternal centriole can concurrently generate multiple daughter centrioles. This mechanism was initially identified in cells treated with the peptide vinyl sulfone proteasome inhibitor Z-L(3)VS. We subsequently found that the formation of more than one daughter at maternal centrioles requires cyclin E/cyclin-dependent kinase 2 as well as Polo-like kinase 4 and that overexpression of these proteins mimics this phenotype in the absence of a proteasome inhibitor. Moreover, we show that the human papillomavirus type 16 E7 oncoprotein stimulates aberrant daughter centriole numbers in part through the formation of more than one daughter centriole at single maternal templates. These results help to explain how oncogenic stimuli can rapidly induce abnormal centriole numbers within a single cell-division cycle and provide insights into the regulation of centriole duplication.
几乎在所有癌症中都能检测到中心体数量异常。然而，中心体扩增背后的分子机制却鲜有研究。基于每个母中心粒在每个细胞分裂周期中作为形成唯一一个子中心粒的模板这一模型，目前普遍的观点是中心粒过度复制源于连续几轮的中心粒复制。在此，我们提供证据表明单个母中心粒可同时产生多个子中心粒。这种机制最初是在用肽乙烯砜蛋白酶体抑制剂Z-L(3)VS处理的细胞中发现的。随后我们发现，母中心粒形成多个子中心粒需要细胞周期蛋白E/细胞周期蛋白依赖性激酶2以及Polo样激酶4，并且在没有蛋白酶体抑制剂的情况下，这些蛋白的过表达会模拟这种表型。此外，我们表明人乳头瘤病毒16型E7癌蛋白部分通过在单个母模板上形成多个子中心粒来刺激异常的子中心粒数量。这些结果有助于解释致癌刺激如何能在单个细胞分裂周期内迅速诱导中心粒数量异常，并为中心粒复制的调控提供了见解。
