title: Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species.
abstract: 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.
authors.affiliation: Department of Clinical Cell Biology and Division of Endocrinology and Metabolism, Chiba University Graduate School of Medicine, Chiba-shi, Chiba 260-8670, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Suzuki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masha V
authors.initials: MV
authors.lastname: Poyurovsky
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nagano
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mayama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohkubo
authors.forename: Maria
authors.initials: M
authors.lastname: Lokshin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hosokawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nagao
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tatsuno
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D005972:Glutaminase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D005972:Glutaminase; D005978:Glutathione