Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
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DOI：
10.1073/pnas.1002459107
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发表时间：
2010-04-20
影响因子：
11.1
通讯作者：
Prives, Carol
中科院分区：
文献类型：
--
作者：
Suzuki, Sawako;Tanaka, Tomoaki;Prives, Carol
我们确定了一个p53靶基因，磷酸盐激活的线粒体谷氨酰胺酶（GLS 2），谷氨酰胺转化为谷氨酸的关键酶，从而谷胱甘肽（GSH）合成和能量产生的调节剂。GLS 2表达以p53依赖的方式响应于DNA损伤或氧化应激而被诱导，并且p53与GLS 2启动子相关联。升高的GLS 2促进谷氨酰胺代谢并降低细胞内活性氧（ROS）水平，导致DNA氧化的总体降低，如通过测量正常和应激细胞中的8-OH-dG含量所确定的。此外，GLS 2或p53的siRNA下调损害GSH依赖性抗氧化系统并增加细胞内ROS水平。GLS 2敲低后的高ROS水平也与p53诱导的细胞死亡的刺激一致。我们认为，GLS 2控制细胞内ROS水平和凋亡反应促进了p53保护细胞免受基因组损伤积累的能力，并允许细胞在轻度和可修复的遗传毒性应激后存活。事实上，GLS 2的过表达减少了肿瘤细胞的生长和集落形成。此外，与正常组织相比，GLS 2表达在肝肿瘤中降低。因此，我们的研究结果为p53的独特代谢作用提供了证据，将谷氨酰胺代谢、能量和ROS稳态联系起来，这可能有助于p53的肿瘤抑制功能。
We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), a key enzyme in conversion of glutamine to glutamate, and thereby a regulator of glutathione (GSH) synthesis and energy production. GLS2 expression is induced in response to DNA damage or oxidative stress in a p53-dependent manner, and p53 associates with the GLS2 promoter. Elevated GLS2 facilitates glutamine metabolism and lowers intracellular reactive oxygen species (ROS) levels, resulting in an overall decrease in DNA oxidation as determined by measurement of 8-OH-dG content in both normal and stressed cells. Further, siRNA down-regulation of either GLS2 or p53 compromises the GSH-dependent antioxidant system and increases intracellular ROS levels. High ROS levels following GLS2 knockdown also coincide with stimulation of p53-induced cell death. We propose that GLS2 control of intracellular ROS levels and the apoptotic response facilitates the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress. Indeed, overexpression of GLS2 reduces the growth of tumor cells and colony formation. Further, compared with normal tissue, GLS2 expression is reduced in liver tumors. Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function.