Overexpression of TDP-43 causes partially p53-dependent G2/M arrest and p53-independent cell death in HeLa cells
Overexpression of TDP-43 causes partially p53-dependent G2/M arrest and p53-independent cell death in HeLa cells
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DOI：
10.1016/j.neulet.2011.11.021
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发表时间：
2012-01-11
影响因子：
2.5
通讯作者：
Matsuoka, Masaaki
中科院分区：
文献类型：
--
作者：
Lee, Kikyo;Suzuki, Hiroaki;Matsuoka, Masaaki
据推测，神经元中交互反应dna结合蛋白43 （TDP-43）的失调与肌萎缩侧索硬化症和泛素化包涵体额颞叶变性的发病机制密切相关。然而，TDP-43在非神经元细胞（如胶质细胞）中的失调是否与这些神经退行性疾病的发病机制有关，尚不明确。主要使用HeLa细胞，我们发现TDP-43的低级别过表达（比内源性表达高2- 5倍）在培养的非神经元细胞中诱导细胞周期阻滞在G2/M期和细胞死亡，这被认为是模仿TDP-43功能的增加。由于p53的激活可能在许多异常情况下诱导G2/M阻滞和/或细胞死亡，我们从p53调控的角度研究了G2/M阻滞的机制。结果表明，在p53功能受损的细胞中，tdp -43诱导的G2/M阻滞减弱，而tdp -43诱导的死亡未减弱。这些数据共同表明，TDP-43以部分依赖p53的方式引起G2/M阻滞，并以不依赖p53的方式引起循环细胞的细胞死亡。由于胶质细胞增殖受损可能导致神经元支持能力下降，这些发现进一步表明，TDP-43功能的获得可能通过诱导胶质细胞周期阻滞和死亡而引起神经毒性。2011爱思唯尔爱尔兰有限公司版权所有。
It has been hypothesized that the dysregulation of transactive response DNA-binding protein-43 (TDP-43) in neurons is closely linked to the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions. However, it remains undefined whether the dysregulation of TDP-43 in non-neuronal cells, such as glial cells, contributes to the pathogenesis of these neurodegenerative diseases. Primarily using HeLa cells, we show that a low-grade overexpression of TDP-43,2-to 5-fold greater than endogenous expression, which is thought to mimic the gain of function of TDP-43, induced cell cycle arrest at the G2/M phase and cell death in cultured non-neuronal cells. Since the activation of p53 may induce G2/M arrest and/or cell death in many abnormal situations, we examined the mechanism underlying G2/M arrest from the standpoint of p53 regulation. It was determined that the TDP-43-induced G2/M arrest was attenuated, while TDP-43-induced death was not attenuated, in cells in which the p53 function was compromised. These data collectively indicate that TDP-43 causes G2/M arrest in a partially p53-dependent manner and it causes cell death in a p53-independent manner in cycling cells. Because it is likely that the impaired proliferation in glial cells causes a decrease in the neuron-supporting ability, these findings further suggests that the gain of function of TDP-43 may cause neurotoxicity by inducing cell cycle arrest and death in glial cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved.