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https://www.readbyqxmd.com/read/27880901/stress-kinase-gcn2-controls-the-proliferative-fitness-and-trafficking-of-cytotoxic-t-cells-independent-of-environmental-amino-acid-sensing
#1
Lee-Ann Van de Velde, Xi-Zhi J Guo, Lidija Barbaric, Amber M Smith, Thomas H Oguin, Paul G Thomas, Peter J Murray
GCN2 is one of four "stress kinases" that block translation by phosphorylating eIF2α. GCN2 is thought to bind uncharged tRNAs to "sense" amino acid availability. In mammals, myeloid cells expressing indoleamine dioxygenases locally deplete tryptophan, which is detected by GCN2 in T cells to cause proliferative arrest. GCN2-deficient T cells were reported to ectopically enter the cell cycle when tryptophan was limiting. Using GCN2-deficient strains crossed to T cell receptor (TCR) transgenic backgrounds, we found GCN2 is essential for induction of stress target genes such as CHOP...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27864078/inappropriate-translation-inhibition-and-p-body-formation-cause-cold-sensitivity-in-tryptophan-auxotroph-yeast-mutants
#2
Lidia Ballester-Tomás, Jose A Prieto, Paula Alepuz, Asier González, Elena Garre, Francisca Randez-Gil
In response to different adverse conditions, most eukaryotic organisms, including Saccharomyces cerevisiae, downregulate protein synthesis through the phosphorylation of eIF2α (eukaryotic initiation factor 2α) by Gcn2, a highly conserved protein kinase. Gcn2 also controls the translation of Gcn4, a transcription factor involved in the induction of amino acid biosynthesis enzymes. Here, we have studied the functional role of Gcn2 and Gcn2-regulating proteins, in controlling translation during temperature downshifts of TRP1 and trp1 yeast cells...
November 15, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27852836/perturbations-in-actin-dynamics-reconfigure-protein-complexes-that-modulate-gcn2-activity-and-promote-an-eif2-response
#3
Richard C Silva, Evelyn Sattlegger, Beatriz A Castilho
Genetic and pharmacological interventions in yeast and mammalian cells have suggested a cross-talk between the actin cytoskeleton and protein synthesis. Regulation of the activity of the translation initiation factor 2 (eIF2) is a paramount mechanism for cells to rapidly adjust the rate of protein synthesis and to trigger reprogramming of gene expression to adapt in response to internal and external cues. Here we show that disruption of F-actin in mammalian cells inhibits translation in a GCN2-dependent manner, correlating with increased levels of uncharged tRNA...
November 16, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27717342/impact-is-a-gcn2-inhibitor-that-limits-lifespan-in-caenorhabditis-elegans
#4
Rafael C Ferraz, Henrique Camara, Evandro A De-Souza, Silas Pinto, Ana Paula F Pinca, Richard C Silva, Vitor N Sato, Beatriz A Castilho, Marcelo A Mori
BACKGROUND: The General Control Nonderepressible 2 (GCN2) kinase is a conserved member of the integrated stress response (ISR) pathway that represses protein translation and helps cells to adapt to conditions of nutrient shortage. As such, GCN2 is required for longevity and stress resistance induced by dietary restriction (DR). IMPACT is an ancient protein that inhibits GCN2. RESULTS: Here, we tested whether IMPACT down-regulation mimics the effects of DR in C. elegans...
October 7, 2016: BMC Biology
https://www.readbyqxmd.com/read/27708226/mitochondrial-dysfunction-enhances-cisplatin-resistance-in-human-gastric-cancer-cells-via-the-ros-activated-gcn2-eif2%C3%AE-atf4-xct-pathway
#5
Sheng-Fan Wang, Meng-Shian Chen, Yueh-Ching Chou, Yune-Fang Ueng, Pen-Hui Yin, Tien-Shun Yeh, Hsin-Chen Lee
Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin...
September 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27633668/integrated-stress-response-of-vertebrates-is-regulated-by-four-eif2%C3%AE-kinases
#6
Shusuke Taniuchi, Masato Miyake, Kazue Tsugawa, Miho Oyadomari, Seiichi Oyadomari
The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2α kinases, namely heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase, (PERK) and general control non-depressible 2 (GCN2), have been identified thus far, and they are known to be activated by heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation, respectively...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27613409/gcn2-and-eif2%C3%AE-phosphorylation-independent-but-atf4-dependent-induction-of-care-containing-genes-in-methionine-deficient-cells
#7
Kevin M Mazor, Martha H Stipanuk
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...
December 2016: Amino Acids
https://www.readbyqxmd.com/read/27577186/the-inhibition-of-protein-translation-mediated-by-atgcn1-is-essential-for-cold-tolerance-in-arabidopsis-thaliana
#8
Linjuan Wang, Houhua Li, Chunzhao Zhao, Shengfei Li, Lingyao Kong, Wenwu Wu, Weisheng Kong, Yan Liu, Yuanyuan Wei, Jian-Kang Zhu, Hairong Zhang
In yeast, the interaction of GCN1 (General Control Non-derepressible 1) with GCN2 enables GCN2 to phosphorylate eIF2α (the alpha subunit of eukaryotic translation initiation factor 2) under a variety of stresses. Here, we cloned AtGCN1, an Arabidopsis homologue of GCN1. We show that AtGCN1 directly interacts with GCN2 and is essential for the phosphorylation of eIF2α under SA, UV, cold stress, and amino acid deprivation conditions. Two mutant alleles, atgcn1-1 and atgcn1-2, which are defective in the phosphorylation of eIF2α, showed increased sensitivity to cold stress, compared with the wild type...
August 31, 2016: Plant, Cell & Environment
https://www.readbyqxmd.com/read/27551491/autophagy-mediated-by-arginine-depletion-activation-of-the-nutrient-sensor-gcn2-contributes-to-interferon-%C3%AE-induced-malignant-transformation-of-primary-bovine-mammary-epithelial-cells
#9
X-J Xia, Y-Y Gao, J Zhang, L Wang, S Zhao, Y-Y Che, C-J Ao, H-J Yang, J-Q Wang, L-C Lei
Autophagy has been linked to the regulation of both the prevention and progression of cancer. IFN-γ has been shown to induce autophagy in multiple cell lines in vitro. However, whether IFN-γ can induce autophagy and whether autophagy promotes malignant transformation in healthy lactating bovine mammary epithelial cells (BMECs) remain unclear. Here, we provide the first evidence of the correlation between IFN-γ treatment, autophagy and malignant transformation and of the mechanism underlying IFN-γ-induced autophagy and subsequent malignant transformation in primary BMECs...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27493214/histidine-regulates-seed-oil-deposition-through-abscisic-acid-biosynthesis-and-%C3%AE-oxidation
#10
Huimin Ma, Shui Wang
The storage compounds are deposited into plant seeds during maturation. As the model oilseed species, Arabidopsis (Arabidopsis thaliana) has long been studied for seed oil deposition. However, the regulation of this process remains unclear. Through genetic screen with a seed oil body-specific reporter, we isolated low oil1 (loo1) mutant. LOO1 was mapped to HISTIDINE BIOSYNTHESIS NUMBER 1A (HISN1A). HISN1A catalyzes the first step of His biosynthesis. Oil significantly decreased, and conversely proteins markedly increased in hisn1a mutants, indicating that HISN1A regulates both oil accumulation and the oil-protein balance...
October 2016: Plant Physiology
https://www.readbyqxmd.com/read/27465797/activation-of-general-control-nonderepressible-2-kinase-protects-human-glomerular-endothelial-cells-from-harmful-high-glucose-induced-molecular-pathways
#11
Theodoros Eleftheriadis, Konstantina Tsogka, Georgios Pissas, Georgia Antoniadi, Vassilios Liakopoulos, Ioannis Stefanidis
PURPOSE: Considering the referred beneficial effects of protein restriction on diabetic nephropathy (DN) and the role of renal endothelium in its pathogenesis, we evaluated the effect of general control nonderepressible 2 (GCN2) kinase activation, a sensor of amino acid deprivation, on known detrimental molecular pathways in primary human glomerular endothelial cells (GEnC). METHODS: GEnC were cultured under normal or high-glucose conditions in the presence or not of the GCN2 kinase activator, tryptophanol...
October 2016: International Urology and Nephrology
https://www.readbyqxmd.com/read/27407108/identification-of-the-mrna-targets-of-trna-specific-regulation-using-genome-wide-simulation-of-translation
#12
Barbara Gorgoni, Luca Ciandrini, Matthew R McFarland, M Carmen Romano, Ian Stansfield
tRNA gene copy number is a primary determinant of tRNA abundance and therefore the rate at which each tRNA delivers amino acids to the ribosome during translation. Low-abundance tRNAs decode rare codons slowly, but it is unclear which genes might be subject to tRNA-mediated regulation of expression. Here, those mRNA targets were identified via global simulation of translation. In-silico mRNA translation rates were compared for each mRNA in both wild-type and a [Formula: see text] sup70-65 mutant, which exhibits a pseudohyphal growth phenotype and a 75% slower CAG codon translation rate...
July 12, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27397084/general-control-non-derepressible-2-gcn2-in-t-cells-controls-disease-progression-of-autoimmune-neuroinflammation
#13
Melanie Keil, Jana K Sonner, Tobias V Lanz, Iris Oezen, Theresa Bunse, Stefan Bittner, Hannah V Meyer, Sven G Meuth, Wolfgang Wick, Michael Platten
Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood. In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation...
August 15, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/27396336/metabolic-responses-to-dietary-protein-restriction-require-an-increase-in-fgf21-that-is-delayed-by-the-absence-of-gcn2
#14
Thomas Laeger, Diana C Albarado, Susan J Burke, Lexus Trosclair, John W Hedgepeth, Hans-Rudolf Berthoud, Thomas W Gettys, J Jason Collier, Heike Münzberg, Christopher D Morrison
FGF21 contributes to the metabolic response to dietary protein restriction, and prior data implicate GCN2 as the amino acid sensor linking protein restriction to FGF21 induction. Here, we demonstrate the persistent and essential role of FGF21 in the metabolic response to protein restriction. We show that Fgf21 KO mice are fully resistant to low protein (LP)-induced changes in food intake, energy expenditure (EE), body weight gain, and metabolic gene expression for 6 months. Gcn2 KO mice recapitulate this phenotype, but LP-induced effects on food intake, EE, and body weight subsequently begin to appear after 14 days on diet...
July 19, 2016: Cell Reports
https://www.readbyqxmd.com/read/27318325/metabolic-adaptation-of-skeletal-muscle-to-hyperammonemia-drives-the-beneficial-effects-of-l-leucine-in-cirrhosis
#15
Gangarao Davuluri, Dawid Krokowski, Bo-Jhih Guan, Avinash Kumar, Samjhana Thapaliya, Dharmvir Singh, Maria Hatzoglou, Srinivasan Dasarathy
BACKGROUND & AIMS: Increased skeletal muscle ammonia uptake with loss of muscle mass adversely affects clinical outcomes in cirrhosis. Hyperammonemia causes reduced protein synthesis and sarcopenia but the cellular responses to impaired proteostasis and molecular mechanism of l-leucine induced adaptation to ammonia induced stress were determined. METHODS: Response to activation of amino acid deficiency sensor, GCN2, in the skeletal muscle from cirrhotic patients and the portacaval anastomosis (PCA) rat were quantified...
November 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27302165/genetic-disruption-of-the-multifunctional-cd98-lat1-complex-demonstrates-the-key-role-of-essential-amino-acid-transport-in-the-control-of-mtorc1-and-tumor-growth
#16
Yann Cormerais, Sandy Giuliano, Renaud LeFloch, Benoît Front, Jerome Durivault, Eric Tambutté, Pierre-André Massard, Laura Rodriguez de la Ballina, Hitoshi Endou, Michael F Wempe, Manuel Palacin, Scott K Parks, Jacques Pouyssegur
The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a potential therapeutic target. This complex promotes tumorigenesis with CD98 (4F2hc) engaging β-integrin signaling while LAT1 (SLC7A5) imports essential amino acids (EAA) and promotes mTORC1 activity. However, it is unclear as to which member of the heterodimer carries the most prevalent protumoral action. To answer this question, we explored the tumoral potential of each member by gene disruption of CD98, LAT1, or both and by inhibition of LAT1 with the selective inhibitor (JPH203) in six human cancer cell lines from colon, lung, and kidney...
August 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27297692/gcn2-contributes-to-mtorc1-inhibition-by-leucine-deprivation-through-an-atf4-independent-mechanism
#17
Julien Averous, Sarah Lambert-Langlais, Florent Mesclon, Valérie Carraro, Laurent Parry, Céline Jousse, Alain Bruhat, Anne-Catherine Maurin, Philippe Pierre, Christopher G Proud, Pierre Fafournoux
It is well known that the GCN2 and mTORC1 signaling pathways are regulated by amino acids and share common functions, in particular the control of translation. The regulation of GCN2 activity by amino acid availability relies on the capacity of GCN2 to sense the increased levels of uncharged tRNAs upon amino acid scarcity. In contrast, despite recent progress in the understanding of the regulation of mTORC1 by amino acids, key aspects of this process remain unsolved. In particular, while leucine is well known to be a potent regulator of mTORC1, the mechanisms by which this amino acid is sensed and control mTORC1 activity are not well defined...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27272383/regulating-the-expression-of-therapeutic-transgenes-by-controlled-intake-of-dietary-essential-amino-acids
#18
Cédric Chaveroux, Alain Bruhat, Valérie Carraro, Céline Jousse, Julien Averous, Anne-Catherine Maurin, Laurent Parry, Florent Mesclon, Yuki Muranishi, Pierre Cordelier, Aline Meulle, Patrick Baril, Anh Do Thi, Philippe Ravassard, Jacques Mallet, Pierre Fafournoux
Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential amino acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized amino acid response elements (AAREs) had low basal expression and high induced expression...
July 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27255611/nutrient-shortage-triggers-the-hexosamine-biosynthetic-pathway-via-the-gcn2-atf4-signalling-pathway
#19
Cédric Chaveroux, Carmen Sarcinelli, Virginie Barbet, Sofiane Belfeki, Audrey Barthelaix, Carole Ferraro-Peyret, Serge Lebecque, Toufic Renno, Alain Bruhat, Pierre Fafournoux, Serge N Manié
The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27248816/a-gcn2-like-eif2%C3%AE-kinase-ldek1-of-leishmania-donovani-and-its-possible-role-in-stress-response
#20
Shilpa J Rao, Shimi Meleppattu, Jayanta K Pal
Translation regulation in Leishmania parasites assumes significance particularly because they encounter myriad of stresses during their life cycle. The eukaryotic initiation factor 2α (eIF2α) kinases, the well-known regulators of translation initiation in higher eukaryotes have now been found to control various processes in these protozoan parasites as well. Here, we report on cloning and characterization of a GCN2-like eIF2α kinase from L. donovani and also on its modulation during nutrient starvation. We cloned a GCN2-like kinase from L...
2016: PloS One
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