Centrosome amplification induced by hydroxyurea leads to aneuploidy in pRB deficient human and mouse fibroblasts
Centrosome amplification induced by hydroxyurea leads to aneuploidy in pRB deficient human and mouse fibroblasts
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DOI：
10.1016/j.canlet.2005.07.005
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发表时间：
2006-07-08
期刊：
影响因子：
9.7
通讯作者：
Di Leonardo, Aldo
中科院分区：
文献类型：
--
作者：
Lentini, Laura;Iovino, Flora;Di Leonardo, Aldo
在人类肿瘤中经常观察到中心体的数量和/或形态的改变。然而，它仍然是有争议的，是否存在直接联系的额外中心体和肿瘤的发生，如果中心体扩增可能直接导致非整倍体。在这里，我们报告说，羟基脲治疗诱导中心体扩增的人成纤维细胞表达的HPV 16-E6-E7癌蛋白，主要通过靶向p53和pRB，分别在条件pRB缺陷的小鼠成纤维细胞。在去除羟基脲后，正常和p53缺陷的人成纤维细胞都被阻滞。相反，pRB缺陷的成纤维细胞进入细胞周期，产生非整倍体细胞。此外，大多数条件性Rb缺陷MEFs表现出额外的中心体和非整倍体细胞，随着时间的推移而增加。最后，我们的研究结果表明，pRB功能障碍在人类和小鼠成纤维细胞短暂地逮捕在GI/S的羟基脲允许中心体扩增，在DNA合成的情况下，这反过来又可以驱动非整倍体。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
Alterations in the number and/or morphology of centrosomes are frequently observed in human tumours. However, it is still debated if a direct link between supernumerary centrosomes and tumorigenesis exists and if centrosome amplification could directly cause aneuploidy. Here, we report that hydroxyurea treatment induced centrosome amplification in both human fibroblasts expressing the HPV16 -E6-E7 oncoproteins, which act principally by targeting p53 and pRB, respectively, and in conditional pRB deficient mouse fibroblasts. Following hydroxyurea removal both normal and p53 deficient human fibroblasts arrested. On the contrary pRB deficient fibroblasts entered the cell cycle generating aneuploid cells. Also the majority of conditional Rb deficient MEFs showed supernumerary centrosomes and aneuploid cells which increased over time. Finally, our results suggest that pRB dysfunction both in human and murine fibroblasts transiently arrested in GI/S by hydroxyurea allows centrosomes amplification, in the absence of DNA synthesis, that in turn could drive aneuploidy. (c) 2005 Elsevier Ireland Ltd. All rights reserved.