ArticleAmino acids2016
GCN2- and eIF2α-phosphorylation-independent, but ATF4-dependent, induction of CARE-containing genes in methionine-deficient cells.
Article in Amino acids, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 41 citations in OpenAlex.
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- Crosstalk between dysregulated amino acid sensing and glucose and lipid metabolism in colorectal cancer.Frontiers in oncology · 2025Review
- Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.GeroScience · 2024Article
- Rescue of Methionine Dependence by Cobalamin in a Human Colorectal Cancer Cell Line.Nutrients · 2024Article
- Effects of Individual Essential Amino Acids on Growth Rates of Young Rats Fed a Low-Protein Diet.Animals : an open access journal from MDPI · 2024Article
- Kinetic proteomics identifies targeted changes in liver metabolism and the ribo-interactome by dietary sulfur amino acid restriction.GeroScience · 2023Article
- Vitamin D Promotes Mucosal Barrier System of Fish Skin Infected withInternational journal of molecular sciences · 2023Article
- Sensing of the non-essential amino acid tyrosine governs the response to protein restriction in Drosophila.Nature metabolism · 2022Article
- Targeting the methionine addiction of cancer.American journal of cancer research · 2022Review
- Role of Proteasomes in Inflammation.Journal of clinical medicine · 2021Review
- Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex.The Journal of nutrition · 2021Article
- The acute transcriptional responses to dietary methionine restriction are triggered by inhibition of ternary complex formation and linked to Erk1/2, mTOR, and ATF4.Scientific reports · 2021Article
- Serine, glycine and one‑carbon metabolism in cancer (Review).International journal of oncology · 2021Review
- Crosstalk between Oxidative Stress and Ferroptosis/Oxytosis in Ischemic Stroke: Possible Targets and Molecular Mechanisms.Oxidative medicine and cellular longevity · 2021Review
- Transcriptional Activation ofNutrients · 2020Article
- Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2020Review
- The Chemical Biology of Ferroptosis in the Central Nervous System.Cell chemical biology · 2020Review
- Seryl-tRNA synthetase is involved in methionine stimulation ofThe British journal of nutrition · 2020Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Amino-acid deprivation is sensed by the eIF2α kinase GCN2. Under conditions of essential amino-acid limitation, GCN2 phosphorylates eIF2α, inhibiting the formation of a new ternary complex and hence mRNA translation initiation. While decreasing global mRNA translation, eIF2α phosphorylation also increases the translation of the integrated stress response (ISR) transcription factor ATF4, which increases the expression of many stress response genes that contain a C/EBP-ATF response element (CARE), including Atf4, 4Ebp1, Asns, and Chop. Using wild-type as well as Gcn2 knockout and unphosphorylatable eIF2α mutant MEFs, we characterized a novel GCN2/eIF2α phosphorylation-independent, but ATF4-dependent, pathway that upregulates the expression of CARE-containing genes in MEFs lacking GCN2 or phosphorylatable eIF2α when these cells are exposed to methionine-deficient, and to a lesser extent arginine- or histidine-deficient, medium. Thus, we demonstrate a GCN2/eIF2α phosphorylation-independent pathway that converges with the GCN2/eIF2α kinase-dependent pathway at the level of ATF4 and similarly results in the upregulation of CARE-containing genes. We hypothesize that the essential role of methionine-charged initiator tRNA in forming ternary complex is responsible for the robust ability of methionine deficiency to induce ATF4 and the ISR even in the absence of GCN2 or eIF2α kinase activity.
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