ArticleProceedings of the National Academy of Sciences of the United States of America2010
Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 423 papers, 2 of them syntheses that pooled it.
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Who cites it
423 citing papers in PubMed, 2 syntheses or guidelines pooled it, 679 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Ferroptosis in glioma treatment: Current situation, prospects and drug applications.Frontiers in oncology · 2022Pooled it
- Metabolic reprogramming in colorectal cancer: Mechanisms and therapeutic insights.Genes & diseases · 2027Review
- Understanding the epigenetic regulation of lactylation and aberrant lactate metabolism in cancer: From mechanisms to therapeutic strategies (Review).International journal of oncology · 2026Review
- Mitochondrial inhibition enhances the sensitivity of pancreatic ductal adenocarcinoma cells to oncolytic adenovirus.Molecular therapy. Oncology · 2026Article
- PYCR1 promotes glutamine metabolism and the progression of lung adenocarcinoma by regulating the expression of OPLAH.Clinical and experimental medicine · 2026Article
- Targeting the mitochondrial thermogenesis pathway for neuroprotection in neonatal hypoxic-ischemic encephalopathy by curcumin.Acta pharmacologica Sinica · 2026Article
- NR4A3 alleviates diabetic neuropathy via GLS2-mediated mitochondrial repair and Schwann cell differentiation.iScience · 2026Article
- Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.Genes & diseases · 2026Review
- Targeting glutamine metabolism to modulate macrophage functions in the tumor microenvironment.Discover oncology · 2026Review
- Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.Amino acids · 2026Review
- Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer.International journal of molecular sciences · 2026Article
- Glutaminase 1 in Vascular Disease: Linking Metabolic Reprogramming to Atherosclerosis Progression and Stability.Journal of cardiovascular translational research · 2026Review
- Pathogenic Mechanisms in Cervical Cancer: Energy Metabolism, Hypoxia and Therapy.Life (Basel, Switzerland) · 2026Review
- Tackling cuproptosis: from metabolic rewiring to therapeutic exploitation in cancer.Cellular & molecular immunology · 2026Review
- Navigating the complexities of ferroptosis in pancreatic ductal adenocarcinoma: roles, mechanisms and potential applications.Cell death discovery · 2026Review
- Targeting Metabolic Vulnerabilities in Glioblastoma: a Framework for Multi-node Combination Therapy.Current oncology reports · 2026Review
- CRIP1 promotes docetaxel resistance and immune-associated cell death modulation in prostate cancer.Frontiers in pharmacology · 2026Article
- The Interdependence of Carbon Substrates and Metabolic Pathways Enables the Metabolic Plasticity of Cancer Cells.Advances in experimental medicine and biology · 2026Review
- Review
363 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
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.
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