Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis (Retracted article. See JAN, 2023)
Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis (Retracted article. See JAN, 2023)
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DOI：
10.1038/sj.cdd.4401420
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发表时间：
2004-08-01
影响因子：
12.4
通讯作者：
Filosa, S
中科院分区：
文献类型：
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作者：
Fico, A;Paglialunga, F;Filosa, S
葡萄糖-6-磷酸脱氢酶缺失的胚胎干细胞（G6pdDelta）在体外没有特殊要求的情况下增殖，但当受到氧化剂的挑战时，不能维持谷胱甘肽二硫再转化为还原性谷胱甘肽（GSH），进入氧化应激状态。在这里，我们研究了G6pdDelta和野生型（wt） ES细胞中GSH氧化下游的信号事件。我们发现G6pdDelta ES细胞对氧化剂非常敏感，在氧化剂浓度下激活凋亡途径，否则对wt ES细胞是亚致死的。我们发现，低氧化浓度激活的凋亡途径伴随着线粒体功能障碍，因此它被Bcl-X-L的过表达阻断。Bcl-X-L不抑制氧化处理后细胞GSH和活性氧形成的减少。我们还发现，在胚胎干细胞的氧化处理之后，会激活MEK/细胞外信号调节激酶（ERK）途径。有趣的是，与wt相比，ERK激活在G6pdDelta ES细胞中具有相反的结果，前者具有促凋亡功能，后者具有促存活功能。我们发现这种现象可以由细胞谷胱甘肽水平调节。
Glucose-6-phosphate dehydrogenase-deleted embryonic stem (ES) cells (G6pdDelta) proliferate in vitro without special requirements, but when challenged with oxidants fail to sustain glutathione disulphide reconversion to reduced glutathione (GSH), entering a condition of oxidative stress. Here, we investigate the signalling events downstream of GSH oxidation in G6pdDelta and wild-type (wt) ES cells. We found that G6pdDelta ES cells are very sensitive to oxidants, activating an apoptotic pathway at oxidant concentrations otherwise sublethal for wt ES cells. We show that the apoptotic pathway activated by low oxidant concentrations is accompanied by mitochondria dysfunction, and it is therefore blocked by the overexpression of Bcl-X-L. Bcl-X-L does not inhibit the decrease in cellular GSH and reactive oxygen species formation following oxidant treatment. We also found that oxidant treatment in ES cells is followed by the activation of the MEK/ extracellular signal-regulated kinase (ERK) pathway. Interestingly, ERK activation has opposite outcomes in G6pdDelta ES cells compared to wt, which has a proapoptotic function in the first and a prosurvival function in the latter. We show that this phenomenon can be regulated by the cellular GSH level.