Radiation response of neural precursor cells: Linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress
Radiation response of neural precursor cells: Linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress
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DOI：
10.1667/rr3112
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发表时间：
2004-01-01
影响因子：
3.4
通讯作者：
Fike, JR
中科院分区：
文献类型：
--
作者：
Limoli, CL;Giedzinski, E;Fike, JR
脑的治疗性照射可导致进行性认知功能障碍，可能涉及神经发生缺陷。为了了解辐射所致干细胞功能障碍的机制，从成年大鼠海马区分离神经前体细胞，分析X射线照射后急性(0-24 h)和慢性(3-33 d)细胞凋亡和活性氧(ROS)的变化。照射后的神经前体细胞表现出急性剂量依赖性的凋亡，并伴随着ROS的增加，并持续3-4周。辐射效应包括激活细胞周期检查点，这些检查点与Trp53磷酸化和Trp53和p21(CDKN1A)蛋白水平升高有关。在体内，海马齿状回颗粒下带内的神经前体细胞对辐射表现出显著的敏感性。增殖的前体细胞及其后代(即未成熟神经元)表现出细胞数量的剂量依赖性减少。这些减少在TrP53基因缺失的小鼠中没有那么严重，可能是由于细胞凋亡的中断。这些数据表明，细胞凋亡和ROS反应可能与TrP53依赖的细胞周期控制和应激激活通路的调控有关。体外和体内细胞凋亡测量之间的时间一致性表明，氧化应激可能为认知障碍发展中辐射诱导的神经发生抑制提供了一种机制解释。(C)2004年，由辐射研究学会提供。
Therapeutic irradiation of the brain can cause a progressive cognitive dysfunction that may involve defects in neurogenesis. In an effort to understand the mechanisms underlying radiation-induced stem cell dysfunction, neural precursor cells isolated from the adult rat hippocampus were analyzed for acute (0-24 h) and chronic (3-33 days) changes in apoptosis and reactive oxygen species (ROS) after exposure to X rays. Irradiated neural precursor cells exhibited an acute dose-dependent apoptosis accompanied by an increase in ROS that persisted over a 3-4-week period. The radiation effects included the activation of cell cycle checkpoints that were associated with increased Trp53 phosphorylation and Trp53 and p21 (Cdkn1a) protein levels. In vivo, neural precursor cells within the hippocampal dentate subgranular zone exhibited significant sensitivity to radiation. Proliferating precursor cells and their progeny (i.e. immature neurons) exhibited dose-dependent reductions in cell number. These reductions were less severe in Trp53-null mice, possibly due to the disruption of apoptosis. These data suggest that the apoptotic and ROS responses may be tied to Trp53-dependent regulation of cell cycle control and stress-activated pathways. The temporal coincidence between in vitro and in vivo measurements of apoptosis suggests that oxidative stress may provide a mechanistic explanation for radiation-induced inhibition of neurogenesis in the development of cognitive impairment. (C) 2004 by Radiation Research Society.