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GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis [CHARGE-seq]

ABSTRACT: GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis [CHARGE-seq]

PROVIDER: PRJNA804111 | ENA |

REPOSITORIES: ENA

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GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis [CHARGE-seq]

Project description:Here we report genome wide tRNA charging analysis (CHARGE seq) on DMSO, GCN2iB and GCN2iB plus essential amino acid (EAA) treated WT LNCaP cells

2022-10-17 | GSE196251 | GEO

GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis

Project description:GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis

| PRJNA804108 | ENA

GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis [mRNA-seq]

Project description:GCN2 enhances the growth and progression of prostate cancer by maintaining amino acid homeostasis [mRNA-seq]

| PRJNA804110 | ENA

The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation

Project description:Circadian clocks are evolved to adapt to the daily environment changes under different conditions. The ability to maintain circadian clock functions in response to various stress and perturbations is important for organismal fitness. Here, we show that the nutrient sensing GCN2 signaling pathway is required for robust circadian clock function under amino acid starvation in Neurospora. The deletion of GCN2 pathway components disrupts rhythmic transcription of clock gene frq by suppressing WC complex binding at the frq promoter due to its reduced histone H3 acetylation levels. Under amino acid starvation, the activation of GCN2 kinase and its downstream transcription factor CPC-1 establish a proper chromatin state at the frq promoter by recruiting the histone acetyltransferase GCN-5. The arrhythmic phenotype of the GCN2 kinase mutants under amino acid starvation can be rescued by inhibiting histone deacetylation. Finally, genome-wide transcriptional analysis indicates that the GCN2 signaling pathway maintains robust rhythmic expression of metabolic genes under amino acid starvation. Together, these results uncover an essential role of GCN2 signaling pathway in maintaining robust circadian clock function in response to amino acid starvation and the importance of histone acetylation at the frq locus in rhythmic gene expression.

2023-05-08 | GSE220169 | GEO

The role of GCN2 kinase in amino acid dependent longevity and feeding behaviour in Drosophila

Project description:Dietary amino acids restriction extends lifespan in diverse species ranging from flies to mammals. The evolutionarily conserved serine/threonine kinase General Control Nonderepressible 2 (GCN2) is a key sensor of amino acid deficiency and has been implicated in lifespan regulation upon dietary restriction. However, the role of individual essential amino acids (EAA) in modulating organismal lifespan and the underlying molecular mechanisms through which EAA mediate these effects are only partially understood. We generated a novel Drosophila GCN2 null mutant and systematically analyzed its response to individual amino acid deficiency.

2022-06-03 | GSE203210 | GEO

The amino acid sensor GCN2 controls red blood cell life cycle and iron metabolism through regulation of tissue resident macrophages

Project description:GCN2 (General Control Nonderepressible 2) is a serine/threonine-protein kinase that controls mRNA translation in response to amino acid availability. Here we show that production and clearance of erythrocytes are controlled by GCN2. Our data highlight the importance of tissue-resident macrophages as the primary cell type mediating this effect. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2-/-) mice displayed resistance to anemia as compared to wild-type (GCN2+/+) mice. GCN2-/- liver macrophages display defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2-/- cells indicates that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating RBC clearance and iron recycling. We performed NRF2 (Nfe2l2) ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.

2022-12-01 | GSE188460 | GEO

Selective control of metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae

Project description:When eukaryotic cells are deprived of amino acids, uncharged tRNAs accumulate and activate the conserved GCN2 protein kinase. We examine how yeast growth and tRNA charging or aminoacylation is affected during amino acid depletion in the presence and absence of GCN2. tRNA charging is measured using a microarray technique which allows for simultaneous measurement of all cytosolic tRNAs. A fully prototrophic and its isogenic GCN2 deletion strain were used. We measured relative tRNA charging levels in yeast strains with an intact and deleted GCN2.

2010-08-01 | E-GEOD-22452 | biostudies-arrayexpress

Coordination between GCN2 eIF2 kinase and p53 signaling supports purine metabolism and enhances growth and progression of prostate cancer

Project description:Cancers invoke response pathways to mitigate external and internal stresses to aid growth and proliferation. For example, we reported that GCN2 eIF2 kinase and the Integrated Stress Response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, while genetic or pharmacological loss of GCN2 lowers intracellular amino acids and deters PCa growth, there does not appear to be appreciable cell death. Using biochemical and molecular approaches, RNA-seq and CRISPRi-based screens, along with in vitro and in vivo PCa models, we discovered that the loss of GCN2 in PCa induces p53 signaling and tumor senescence. Activation of p53 occurs by reductions in purine nucleobases and lowered rRNA synthesis that induce the Impaired Ribosome Biogenesis Checkpoint. Loss of GCN2 combined with depletion of p53 or pharmacological inhibition of de novo purine biosynthesis with the GART inhibitor pelitrexol sharply reduces PCa growth and triggers apoptosis, emphasizing the importance of coordinated GCN2 and p53 regulation and their utility in PCa therapeutics.

2024-10-01 | GSE260934 | GEO

GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency

Project description:Disruptions in circadian rhythms are associated with increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole-body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24 h feeding fasting cycle. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a Control or leucine-devoid diet (LeuD) for 8-days in total darkness. On the last day, blood and livers were collected at circadian time (CT) 3 and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched chain amino acid concentrations (r2=0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillation in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Further, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole-body metabolism.

2024-08-27 | GSE262319 | GEO

Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions

Project description:Diverse environmental insults induce the integrated stress response (ISR), which features eIF2 phosphorylation and translational control that serves to restore protein homeostasis. The eIF2 kinase GCN2 is a first responder in the ISR that is activated by amino acid depletion and other unrelated stresses. Two processes are suggested to trigger an ordered process of GCN2 activation during stress: GCN2 monitoring stress via accumulating uncharged tRNAs or by stalled and colliding ribosomes. Our results suggest that while ribosomal collisions are indeed essential for GCN2 activation in response to translational elongation inhibitors, conditions that trigger deacylation of tRNAs activate GCN2 via its direct association with affected tRNAs. Both process require the GCN2 regulatory domain related to histidyl tRNA synthetases. GCN2 activation by UV irradiation features lowered amino acids and increased uncharged tRNAs and ribosome collisions are dispensable. We conclude that there are multiple mechanisms that activate GCN2 during diverse stresses.

2024-03-06 | GSE239867 | GEO

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