Cell Death and Human Disease Group, Division of Cancer and Developmental Cell Biology, Institute of Molecular and Cell Biology, Singapore.
Neurosci Lett. 2009 Dec 31;467(3):241-6. doi: 10.1016/j.neulet.2009.10.050. Epub 2009 Oct 21.
Studies have shown that nitric oxide (NO)-induced apoptosis is mediated by a variety of cellular signaling pathways. However, the information is relatively limited to neural progenitor cells (NPCs). In this study, the role of p53 in the NO-induced apoptosis was examined in an in vitro model of NPCs. Comparisons were made between NPCs derived from either wild type or p53 knockout mice brain stimulated by diethylenetriamine/nitric oxide adduct (DETA/NO), an established NO donor that constantly releases NO through its known first order pharmacological kinetics and prolonged half-life. We found that treatment by DETA/NO both time- and dose-dependently induced a significant increase of apoptosis in wild type NPCs, while p53 knockout NPCs were resistant to the DETA/NO challenge. In addition, the DETA/NO-triggered alteration of mitochondrial membrane permeability, cleavage of caspase-9/3, and expression of pro-apoptotic Bcl-2 family members noxa and puma occurred in wild type NPCs but not in p53 knockout NPCs. Our current results suggest a central role of p53 in the NO-induced apoptotic pathway in NPCs, which may hence provide new insights into the regulation of cell death in NPCs that respond to overproduction of NO in injured brain.
研究表明，一氧化氮（NO）诱导的细胞凋亡是通过多种细胞信号通路介导的。然而，关于神经祖细胞（NPC）的信息相对较少。在这项研究中，我们在体外 NPC 模型中研究了 p53 在 NO 诱导的细胞凋亡中的作用。我们比较了来自野生型或 p53 敲除小鼠大脑的 NPC 在二乙三胺/一氧化氮加合物（DETA/NO）刺激下的作用，DETA/NO 是一种已建立的 NO 供体，通过其已知的一阶药理学动力学和延长的半衰期持续释放 NO。我们发现，DETA/NO 的处理时间和剂量依赖性地诱导野生型 NPC 中显著增加细胞凋亡，而 p53 敲除 NPC 对 DETA/NO 挑战具有抗性。此外，DETA/NO 触发的线粒体膜通透性改变、半胱天冬酶-9/3 的切割以及促凋亡 Bcl-2 家族成员 noxa 和 puma 的表达仅发生在野生型 NPC 中，而在 p53 敲除 NPC 中未发生。我们目前的结果表明，p53 在 NPC 中 NO 诱导的凋亡途径中起核心作用，这可能为受伤大脑中 NO 过度产生时 NPC 中细胞死亡的调节提供新的见解。
