Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors
Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors
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DOI：
10.4161/cc.10.14.16310
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发表时间：
2011-07-15
期刊：
影响因子：
4.3
通讯作者：
Dai, Wei
中科院分区：
文献类型：
--
作者：
Hu, Liyan;Liu, Xin;Dai, Wei
细胞周期检查点的破坏和正常细胞周期进程的干扰经常导致细胞死亡或恶性转化。六价铬 [Cr(VI)] 是一种众所周知的致癌物质，与多种人类恶性肿瘤（包括肺癌）的发生有关。然而，Cr(VI)引起肺部恶变的确切机制仍不清楚。我们已经证明，长期暴露于非细胞毒性浓度的 Cr(VI) 会诱导多种染色体异常，包括姐妹染色单体过早分离、染色体断裂以及滞后/错位染色体的存在。用诺考达唑治疗后，HeLa 和正常肺支气管上皮细胞均停止有丝分裂。然而，Cr(VI) 显着损害诺考达唑诱导的 M 期停滞。 Cr(VI) 抑制 BubR1 激活并减少 Emi1 表达，导致 APC/C 意外激活。与这一观察结果一致，Cr(VI) 处理导致有丝分裂释放过程中 Geminin 的多泛素化增强，同时解除了 DNA 复制许可因子 Cdt1 活性的调节。综合起来，这些结果表明 Cr(VI) 诱导的染色体不稳定部分是由于 APC/C 活性的扰动，从而导致染色体不稳定。
Disruption of cell cycle checkpoints and interference with the normal cell cycle progression frequently result in cell death or malignant transformation. Hexavalent chromium [Cr(VI)] is a well-known carcinogen that has been implicated in the occurrence of many types of human malignancies, including lung cancer. However, the exact mechanism by which Cr(VI) causes malignant transformation in the lung remains unknown. We have demonstrated that chronic exposure to a non-cytotoxic concentration of Cr(VI) induced a variety of chromosomal abnormalities, including premature sister chromatid separation, chromosomal breakage and the presence of lagging/misaligned chromosomes. After treatment with nocodazole, both HeLa and normal lung bronchial epithelial cells were arrested at mitosis. However, Cr(VI) significantly compromised M-phase arrest induced by nocodazole. Cr(VI) suppressed BubR1 activation and reduced expression of Emi1, leading to an unscheduled activation of APC/C. Consistent with this observation, Cr(VI) treatment caused enhanced polyubiquitination of geminin during mitotic release while it deregulated the activity of Cdt1, a DNA replication licensing factor. Combined, these results suggest that Cr(VI)-induced chromosomal instability is partly due to a perturbation of APC/C activities, leading to chromosomal instability.