ArticleNucleic acids research2021
Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
32 citing papers in PubMed, 44 citations in OpenAlex.
- Substrate Binding Relieves Autoinhibition of the Mammalian GCN2 Kinase.bioRxiv : the preprint server for biology · 2026Article
- Amino Acid Metabolism in Health and Disease.MedComm · 2026Review
- The PERK-GADD45A axis is a key driver of hepatic stellate cell activation.Hepatology communications · 2026Article
- Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.RNA (New York, N.Y.) · 2026Article
- Metabolic and transcriptional plasticity supports CD8Immunity · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 2026Article
- Caloric Restriction Enhances the Efficacy of Antiandrogen Therapy in Prostate Cancer by Inhibiting Androgen Receptor Translation.Cancer research · 2025Article
- Differential cell survival outcomes in response to diverse amino acid stress.Life science alliance · 2025Article
- Activation of the integrated stress response and loss of cFLIPCell death discovery · 2025Article
- The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21.Science advances · 2025Article
- The Central FacilitaTOR: Coordinating Transcription and Translation in Eukaryotes.International journal of molecular sciences · 2025Review
- New insights on anti-tumor immunity of CD8Journal of translational medicine · 2025Review
- UPRmt-regulated mitokines: novel strategies for myocardial injury repair.Frontiers in cell and developmental biology · 2025Review
- Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.The Journal of cell biology · 2024Article
- GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.American journal of physiology. Endocrinology and metabolism · 2024Article
- Computational modeling of the synergistic role of GCN2 and the HPA axis in regulating the integrated stress response in the central circadian timing system.Physiological genomics · 2024Article
- Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.Nucleic acids research · 2024Article
- Stress and Liver Fibrogenesis: Understanding the Role and Regulation of Stress Response Pathways in Hepatic Stellate Cells.The American journal of pathology · 2023Review
- Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response.Antioxidants & redox signaling · 2023Review
- Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress.Molecular cancer research : MCR · 2023Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling. Deletion of GCN2 reduced cell survival to HF whereas pharmacological inhibition of mTORC1 afforded protection. HF treatment of mice synchronously activated the GCN2-mediated ISR and mTORC1 in liver whereas Gcn2-null mice allowed greater mTORC1 activation to HF, resulting in liver steatosis and cell death. We conclude that HF causes an amino acid imbalance that uniquely activates both GCN2 and mTORC1. Loss of GCN2 during HF creates a disconnect between metabolic state and need, triggering proteostasis collapse.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.