Tichy Elisia D, Stephan Zachary A, Osterburg Andrew, Noel Greg, Stambrook Peter J
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Stem Cell Res. 2013 May;10(3):428-41. doi: 10.1016/j.scr.2013.01.010. Epub 2013 Feb 5.
Embryonic stem cells (ESCs) are hypersensitive to many DNA damaging agents and can rapidly undergo cell death or cell differentiation following exposure. Treatment of mouse ESCs (mESCs) with etoposide (ETO), a topoisomerase II poison, followed by a recovery period resulted in massive cell death with characteristics of a programmed cell death pathway (PCD). While cell death was both caspase- and necroptosis-independent, it was partially dependent on the activity of lysosomal proteases. A role for autophagy in the cell death process was eliminated, suggesting that ETO induces a novel PCD pathway in mESCs. Inhibition of p53 either as a transcription factor by pifithrin α or in its mitochondrial role by pifithrin μ significantly reduced ESC death levels. Finally, EndoG was newly identified as a protease participating in the DNA fragmentation observed during ETO-induced PCD. We coined the term charontosis after Charon, the ferryman of the dead in Greek mythology, to refer to the PCD signaling events induced by ETO in mESCs.
胚胎干细胞（ESC）对许多DNA损伤剂高度敏感，暴露后可迅速发生细胞死亡或细胞分化。用拓扑异构酶II毒药依托泊苷（ETO）处理小鼠胚胎干细胞（mESC），随后经过恢复期，会导致大量细胞死亡，呈现程序性细胞死亡途径（PCD）的特征。虽然细胞死亡既不依赖于半胱天冬酶也不依赖于坏死性凋亡，但部分依赖于溶酶体蛋白酶的活性。自噬在细胞死亡过程中的作用被排除，这表明ETO在mESC中诱导了一种新的PCD途径。用pifithrinα抑制p53作为转录因子的活性，或用pifithrinμ抑制其线粒体作用，均显著降低了ESC的死亡水平。最后，EndoG被新鉴定为一种参与ETO诱导的PCD过程中观察到的DNA片段化的蛋白酶。我们以希腊神话中冥河船夫卡戎（Charon）的名字创造了“卡戎病”一词，来指代ETO在mESC中诱导的PCD信号事件。
