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https://www.readbyqxmd.com/read/29337352/genetic-removal-of-eif2%C3%AE-kinase-perk-in-mice-enables-hippocampal-l-ltp-independent-of-mtorc1-activity
#1
Helena R Zimmermann, Wenzhong Yang, Brenna C Beckelman, Nicole P Kasica, Xueyan Zhou, Lucas Galli, Alexey G Ryazanov, Tao Ma
Characterization of the molecular signaling pathways underlying protein synthesis-dependent forms of synaptic plasticity, such as late long-term potentiation (L-LTP), can provide insights not only into memory expression/maintenance under physiological conditions but also potential mechanisms associated with the pathogenesis of memory disorders. Here, we report in mice that L-LTP failure induced by the mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) inhibitor rapamycin is reversed by brain-specific genetic deletion of PKR-like ER kinase, PERK (PERK KO), a kinase for eukaryotic initiation factor 2α (eIF2α)...
January 16, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29326164/the-glutamine-transporter-asct2-slc1a5-promotes-tumor-growth-independently-of-the-amino-acid-transporter-lat1-slc7a5
#2
Yann Cormerais, Pierre André Massard, Milica Vucetic, Sandy Giuliano, Eric Tambutté, Jerome Durivault, Valérie Vial, Hitoshi Endou, Michael F Wempe, Scott K Parks, Jacques Pouyssegur
The transporters for glutamine and essential amino acids (EAA), ASCT2 (solute carrier family 1 member 5, SLC1A5), and LAT1 (solute carrier family 7 member 5, SLC7A5), respectively are overexpressed in aggressive cancers and have been identified as cancer-promoting targets. Moreover, previous work has suggested that glutamine influx via ASCT2 triggers EAA entry via the LAT1 exchanger, thus activating mechanistic target of rapamycin complex 1 (mTORC1) and stimulating growth. Here, to further investigate whether these two transporters are functionally coupled, we compared the respective knockout (KO) of either LAT1 or ASCT2 in colon (LS174T) and lung (A549) adenocarcinoma cell lines...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29281830/oncogenic-myc-activates-a-feedforward-regulatory-loop-promoting-essential-amino-acid-metabolism-and-tumorigenesis
#3
Ming Yue, Jue Jiang, Peng Gao, Hudan Liu, Guoliang Qing
Most tumor cells exhibit obligatory demands for essential amino acids (EAAs), but the regulatory mechanisms whereby tumor cells take up EAAs and EAAs promote malignant transformation remain to be determined. Here, we show that oncogenic MYC, solute carrier family (SLC) 7 member 5 (SLC7A5), and SLC43A1 constitute a feedforward activation loop to promote EAA transport and tumorigenesis. MYC selectively activates Slc7a5 and Slc43a1 transcription through direct binding to specific E box elements within both genes, enabling effective EAA import...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29166596/the-gcn2-atf4-signaling-pathway-induces-4e-bp-to-bias-translation-and-boost-antimicrobial-peptide-synthesis-in-response-to-bacterial-infection
#4
Deepika Vasudevan, Nicholas K Clark, Jessica Sam, Victoria C Cotham, Beatrix Ueberheide, Michael T Marr, Hyung Don Ryoo
Bacterial infection often leads to suppression of mRNA translation, but hosts are nonetheless able to express immune response genes through as yet unknown mechanisms. Here, we use a Drosophila model to demonstrate that antimicrobial peptide (AMP) production during infection is paradoxically stimulated by the inhibitor of cap-dependent translation, 4E-BP (eIF4E-binding protein; encoded by the Thor gene). We found that 4E-BP is induced upon infection with pathogenic bacteria by the stress-response transcription factor ATF4 and its upstream kinase, GCN2...
November 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/29153034/advances-in-maldi-mass-spectrometry-within-drug-discovery
#5
Dale S Cornett, Michael D Scholle
Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain...
December 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29129276/amino-acid-modulation-of-lifespan-and-reproduction-in-drosophila
#6
REVIEW
Katja M Hoedjes, Marisa A Rodrigues, Thomas Flatt
Manipulating amino acid (AA) intake in Drosophila can profoundly affect lifespan and reproduction. Remarkably, AA manipulation can uncouple the commonly observed trade-off between these traits. This finding seems to challenge the idea that this trade-off is due to competitive resource allocation, but here we argue that this view might be too simplistic. We also discuss the mechanisms of the AA response, mediated by the IIS/TOR and GCN2 pathways. Elucidating how these pathways respond to specific AA will likely yield important insights into how AA modulate the reproduction-lifespan relationship...
October 2017: Current Opinion in Insect Science
https://www.readbyqxmd.com/read/29118075/translational-control-of-a-human-cdkn1a-mrna-splice-variant-regulates-the-fate-of-uvb-irradiated-human-keratinocytes
#7
Ann E Collier, Dan F Spandau, Ronald C Wek
In response to sublethal UVB irradiation, human keratinocytes transiently block progression of the cell cycle to allow ample time for DNA repair and cell fate determination. These cellular activities are important for evading the initiation of carcinogenesis in skin. Central to these processes is the repression of initiation of mRNA translation through GCN2 phosphorylation of eIF2α (eIF2α-P). Concurrent with reduced global protein synthesis, eIF2α-P and the accompanying Integrated stress response (ISR) selectively enhance translation of mRNAs involved in stress adaptation...
November 8, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29108819/pulmonary-vascular-remodeling-patterns-and-expression-of-general-control-nonderepressible-2-gcn2-in-pulmonary-veno-occlusive-disease
#8
Esther J Nossent, Fabrice Antigny, David Montani, Harm Jan Bogaard, Maria Rosa Ghigna, Mélanie Lambert, Vincent Thomas de Montpréville, Barbara Girerd, Xavier Jaïs, Laurent Savale, Olaf Mercier, Elie Fadel, Florent Soubrier, Olivier Sitbon, Gérald Simonneau, Anton Vonk Noordegraaf, Marc Humbert, Frédéric Perros, Peter Dorfmüller
BACKGROUND: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. METHODS: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry...
October 4, 2017: Journal of Heart and Lung Transplantation
https://www.readbyqxmd.com/read/29079776/sulfur-availability-regulates-plant-growth-via-glucose-tor-signaling
#9
Yihan Dong, Marleen Silbermann, Anna Speiser, Ilaria Forieri, Eric Linster, Gernot Poschet, Arman Allboje Samami, Mutsumi Wanatabe, Carsten Sticht, Aurelio A Teleman, Jean-Marc Deragon, Kazuki Saito, Rüdiger Hell, Markus Wirtz
Growth of eukaryotic cells is regulated by the target of rapamycin (TOR). The strongest activator of TOR in metazoa is amino acid availability. The established transducers of amino acid sensing to TOR in metazoa are absent in plants. Hence, a fundamental question is how amino acid sensing is achieved in photo-autotrophic organisms. Here we demonstrate that the plant Arabidopsis does not sense the sulfur-containing amino acid cysteine itself, but its biosynthetic precursors. We identify the kinase GCN2 as a sensor of the carbon/nitrogen precursor availability, whereas limitation of the sulfur precursor is transduced to TOR by downregulation of glucose metabolism...
October 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29065505/kinases-of-eif2a-switch-translation-of-mrna-subset-during-neuronal-plasticity
#10
REVIEW
Ekaterina Chesnokova, Natalia Bal, Peter Kolosov
Compared to other types of cells, neurons express the largest number of diverse mRNAs, including neuron-specific ones. This mRNA diversity is required for neuronal function, memory storage, maintenance and retrieval. Regulation of translation in neurons is very complicated and involves various proteins. Some proteins, implementing translational control in other cell types, are used by neurons for synaptic plasticity. In this review, we discuss the neuron-specific activity of four kinases: protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), general control nonderepressible 2 kinase (GCN2), and heme-reguated eIF2α kinase (HRI), the substrate for which is α-subunit of eukaryotic initiation factor 2 (eIF2α)...
October 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29046316/evidence-for-the-presence-in-rainbow-trout-brain-of-amino-acid-sensing-systems-involved-in-the-control-of-food-intake
#11
Sara Comesana, Cristina Velasco, Rosa M Ceinos, Marcos A Lopez-Patiño, Jesus M Miguez, Sofia Morais, Jose L Soengas
To assess the existence of central amino acid sensing systems in fish we carried out two experiments in rainbow trout. In the first one, we injected ICV two different branched-chain amino acids (BCAA), leucine and valine, and assessed food intake up to 48 h later. Leucine decreased and valine increased food intake. In a second experiment, 6h after similar ICV treatment we determined changes in parameters related to putative amino acid sensing systems. Amino acid sensing systems respond to leucine in hypothalamus and telencephalon, and to valine in telencephalon...
October 18, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29021785/amino-acid-sensor-kinase-gcn2-is-required-for-conidiation-secondary-metabolism-and-cell-wall-integrity-in-the-taxol-producer-pestalotiopsis-microspora
#12
Dan Wang, Oren Akhberdi, Xiaoran Hao, Xi Yu, Longfei Chen, Yanjie Liu, Xudong Zhu
The canonical Gcn2/Cpc1 kinase in fungi coordinates the expression of target genes in response to amino acid starvation. To investigate its possible role in secondary metabolism, we characterized a gcn2 homolog in the taxol-producing fungus Pestalotiopsis microspora. Deletion of the gene led to severe physiological defects under amino acid starvation, suggesting a conserved function of gcn2 in amino acid sensing. The mutant strain Δgcn2 displayed retardation in vegetative growth. It generated dramatically fewer conidia, suggesting a connection between amino acid metabolism and conidiation in this fungus...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28963559/herbicide-glufosinate-inhibits-yeast-growth-and-extends-longevity-during-wine-fermentation
#13
Beatriz Vallejo, Cecilia Picazo, Helena Orozco, Emilia Matallana, Agustín Aranda
Glufosinate ammonium (GA) is a widely used herbicide that inhibits glutamine synthetase. This inhibition leads to internal amino acid starvation which, in turn, causes the activation of different nutrient sensing pathways. GA also inhibits the enzyme of the yeast Saccharomyces cerevisiae in such a way that, although it is not used as a fungicide, it may alter yeast performance in industrial processes like winemaking. We describe herein how GA indeed inhibits the yeast growth of a wine strain during the fermentation of grape juice...
September 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28894140/d-serine-a-novel-uremic-toxin-induces-senescence-in-human-renal-tubular-cells-via-gcn2-activation
#14
Akira Okada, Masaomi Nangaku, Tzu-Ming Jao, Hiroshi Maekawa, Yu Ishimono, Takahisa Kawakami, Reiko Inagi
The prevalence of chronic kidney disease (CKD), characterized by progressive renal dysfunction with tubulointerstitial fibrosis, is increasing because of societal aging. Uremic toxins, accumulated during renal dysfunction, cause kidney damage, leading to renal deterioration. A recent metabolomic analysis revealed that plasma D-serine accumulation is associated with faster progression of renal dysfunction in CKD patients. However, the causal relationship and the underlying mechanisms remain unclear. Herein, we demonstrated that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28810702/the-nutrient-transceptor-pka-pathway-functions-independently-of-tor-and-responds-to-leucine-and-gcn2-in-a-tor-independent-manner
#15
Michaela Conrad, Harish Nag Kankipati, Marlies Kimpe, Griet Van Zeebroeck, Zhiqiang Zhang, Johan M Thevelein
Two nutrient-controlled signalling pathways, the PKA and TOR pathway, play a major role in nutrient regulation of growth as well as growth-correlated properties in yeast. The relationship between the two pathways is not well understood. We have used Gap1 and Pho84 transceptor-mediated activation of trehalase and phosphorylation of fragmented Sch9 as a read-out for rapid nutrient activation of PKA or TORC1, respectively. We have identified conditions in which L-citrulline-induced activation of Sch9 phosphorylation is compromised, but not activation of trehalase: addition of the TORC1 inhibitor, rapamycin and low levels of L-citrulline...
August 1, 2017: FEMS Yeast Research
https://www.readbyqxmd.com/read/28771613/activation-of-gcn2-in-response-to-different-stresses
#16
Silje Anda, Róbert Zach, Beáta Grallert
All organisms have evolved pathways to respond to different forms of cellular stress. The Gcn2 kinase is best known as a regulator of translation initiation in response to starvation for amino acids. Work in budding yeast has showed that the molecular mechanism of GCN2 activation involves the binding of uncharged tRNAs, which results in a conformational change and GCN2 activation. This pathway requires GCN1, which ensures delivery of the uncharged tRNA onto GCN2. However, Gcn2 is activated by a number of other stresses which do not obviously involve accumulation of uncharged tRNAs, raising the question how Gcn2 is activated under these conditions...
2017: PloS One
https://www.readbyqxmd.com/read/28677085/role-of-saccharomyces-cerevisiae-tan1-trna-acetyltransferase-in-eukaryotic-initiation-factor-2b-eif2b-mediated-translation-control-and-stress-response
#17
Sonum Sharma, Anuradha Sourirajan, Kamal Dev
Eukaryotic initiation factor 2B (eIF2B) controls the first step of translation by catalyzing guanine nucleotide exchange on eukaryotic initiation factor 2 (eIF2). Mutations in the genes encoding eIF2B subunits inhibit the nucleotide exchange and eventually slow down the process of translation, causing vanishing white matter disease. We constructed a Saccharomyces cerevisiae genomic DNA library in YEp24 vector and screened it for the identification of extragenic suppressors of eIF2B mutations, corresponding to human eIF2B mutations...
July 2017: 3 Biotech
https://www.readbyqxmd.com/read/28667176/mir-212-5p-suppresses-lipid-accumulation-by-targeting-fas-and-scd1
#18
Yajie Guo, Junjie Yu, Chunxia Wang, Kai Li, Bin Liu, Ying Du, Fei Xiao, Shanghai Chen, Feifan Guo
MicroRNAs, a class of small non-coding RNAs, are implicated in controlling a variety of biological processes. We have shown that leucine deprivation suppresses lipogenesis by inhibiting fatty acid synthase (FAS) expression in the liver previously; the aim of our current study is to investigate which kind of microRNA is involved in the regulation of FAS expression in response to leucine deprivation. Here, we indicated that microRNA-212-5p specifically binds to mouse FAS 3'UTR and inhibits its activity. Leucine deficiency significantly increased the mRNA levels of miR-212-5p in the livers of mice...
June 30, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28557618/microenvironment-tumor-metabolic-interactions-highlighted-by-qmsi-application-to-the-tryptophan-kynurenine-pathway-in-immuno-oncology
#19
Rima Ait-Belkacem, Vanesa Bol, Gregory Hamm, Florence Schramme, Benoit Van Den Eynde, Lauranne Poncelet, Fabien Pamelard, Jonathan Stauber, Bruno Gomes
Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain...
May 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28536474/gcn2-phosphorylates-hiv-1-integrase-and-decreases-hiv-1-replication-by-limiting-viral-integration
#20
A Jaspart, C Calmels, O Cosnefroy, P Bellecave, P Pinson, S Claverol, V Guyonnet-Dupérat, B Dartigues, M S Benleulmi, E Mauro, P A Gretteau, V Parissi, M Métifiot, M L Andreola
GCN2 is a serine/threonine kinase involved in cellular stress response related to amino acid starvation. Previously, we showed that GCN2 interacts with HIV-1 integrase and is activated during HIV-1 infection. Herein, we identified HIV-1 integrase as a previously unknown substrate of GCN2 in vitro with a major site of phosphorylation at residue S255 located in the C-terminal domain of HIV-1 integrase. The underlying mechanism was investigated and it appeared that the integrase active site was required in order for GCN2 to target the integrase residue S255...
May 23, 2017: Scientific Reports
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