Manganese induces p21 expression in PC12 cells at the transcriptional level
Manganese induces p21 expression in PC12 cells at the transcriptional level
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DOI：
10.1016/j.neuroscience.2012.04.027
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发表时间：
2012-07
期刊：
影响因子：
3.3
通讯作者：
F. Zhao;J-B Zhang;Tongjian Cai;X.Q. Liu;Mc Liu;T. Ke;J.Y. Chen;W. Luo
中科院分区：
文献类型：
--
作者：
F. Zhao;J-B Zhang;Tongjian Cai;X.Q. Liu;Mc Liu;T. Ke;J.Y. Chen;W. Luo
锰是一种常见的环境和职业污染物。过量摄入锰会导致被称为锰中毒的毒性。近年来的研究表明，中枢神经系统细胞周期蛋白的异常表达和细胞周期进程的异常参与了神经退行性疾病的发病机制。本研究旨在探讨锰暴露后p21是否被诱导及其在体外的潜在影响，并着重于了解在这一过程中锰诱导p21的潜在调控机制。我们发现，锰可诱导黑质纹状体区DAR细胞损伤和p21水平上调。用锰处理PC12细胞后，细胞活力随时间和浓度的增加而降低。细胞周期分析表明，锰通过使细胞周期停滞于G2/M期而阻止细胞周期的进展。此外，锰处理使p21的mRNA和蛋白水平升高，但对其他相关因子没有同样的影响。RNA干扰沉默p21显示，锰引起的G2/M期停滞和细胞活力下降均明显逆转。锰不能稳定p21蛋白和p21基因的表达，导致p21基因表达水平显著升高，启动子活性增强，提示可能是一种转录机制。总体而言，体内和体外数据表明，暴露于锰可以增加p21的水平。锰可通过上调p21的表达诱导PC12细胞周期状态的改变，p21的诱导通过启动子的激活和mRNA的诱导在转录水平发生。
Manganese is a common environmental and occupational pollutant. Excessive intake of manganese can cause toxicity known as manganism. Recently it has been demonstrated that unusual expression of cell cycle proteins and aberrant cell cycle progression in the central nervous system are involved in the pathogenesis of neurodegenerative diseases. The present studies were initiated to investigate whether p21 are induced after manganese exposure and its potential effects in vitro, with particular attention being given to understand the underlying regulatory mechanism of p21 induction by manganese in this process. We found that manganese induced DAergic cells injury and upregulation of p21 levels in nigrostriatal regions. Treatment of the PC12 cells with manganese resulted in a time- and concentration-dependent loss of cell viability. Analysis of cell cycle profile indicated that manganese blocked cell cycle progression by arresting the cell cycle at G2/M phase. Moreover, manganese treatment resulted in an increase in the mRNA and protein levels of p21, but did not have the same effect on other related factors. Silencing p21 by RNA interference showed a marked reversal of both G2/M arrest and the decrease in cell viability induced by manganese. Manganese did not stabilize the p21 protein and mRNA, and caused a marked increase in p21 mRNA levels together with an increase in its promoter activity, indicating a transcriptional mechanism. Overall, the in vivo and in vitro data suggest that exposure to manganese can increase p21 levels. An altered cell cycle status of PC12 cells can be induced by manganese through p21 up-regulation, and the induction of p21 occurs at the transcriptional level via promoter activation and mRNA induction.