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https://www.readbyqxmd.com/read/29153034/advances-in-maldi-mass-spectrometry-within-drug-discovery
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
https://www.readbyqxmd.com/read/28528168/human-keratinocyte-differentiation-requires-translational-control-by-the-eif2%C3%AE-%C3%A2-kinase-gcn2
#17
Ann E Collier, Ronald C Wek, Dan F Spandau
Appropriate and sequential differentiation of keratinocytes is essential for all functions of the human epidermis. Although transcriptional regulation has proven to be important for keratinocyte differentiation, little is known about the role of translational control. A key mechanism for modulating translation is through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2). A family of different eIF2α kinases function in the integrative stress response to inhibit general protein synthesis coincident with preferential translation of select mRNAs that participate in stress alleviation...
September 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28526057/recognition-of-a-structural-domain-rwdbd-in-gcn1-proteins-that-interacts-with-the-rwd-domain-containing-proteins
#18
Ramachandran Rakesh, Rangachari Krishnan, Evelyn Sattlegger, Narayanaswamy Srinivasan
The protein Gcn1 (General control non-derepressible 1) is found in virtually all eukaryotes, and is a key component of the general amino acid control signal transduction pathway. This pathway is best known for its importance for cells to sense and overcome amino acid starvation. Gcn1 directly binds to the RWD (RING finger-containing proteins, WD-repeat-containing proteins, and yeast DEAD (DEXD)-like helicases) domain of the protein kinase Gcn2, and this is essential for delivering the starvation signal to Gcn2...
May 19, 2017: Biology Direct
https://www.readbyqxmd.com/read/28465428/hiv-exploits-antiviral-host-innate-gcn2-atf4-signaling-for-establishing-viral-replication-early-in-infection
#19
Guochun Jiang, Clarissa Santos Rocha, Lauren A Hirao, Erica A Mendes, Yuyang Tang, George R Thompson, Joseph K Wong, Satya Dandekar
Antiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production. Less is known about mechanisms by which viral pathogens subvert host antiviral innate responses for establishing their replication and dissemination. We investigated early innate defense against human immunodeficiency virus (HIV) infection and viral evasion by utilizing human CD4(+) T cell cultures in vitro and a simian immunodeficiency virus (SIV) model of AIDS in vivo Our data showed that early host innate defense against the viral infection involves GCN2-ATF4 signaling-mediated suppression of global protein synthesis, which is exploited by the virus for supporting its own replication during early viral infection and dissemination in the gut mucosa...
May 2, 2017: MBio
https://www.readbyqxmd.com/read/28455513/role-of-activating-transcription-factor-4-in-the-hepatic-response-to-amino-acid-depletion-by-asparaginase
#20
Rana J T Al-Baghdadi, Inna A Nikonorova, Emily T Mirek, Yongping Wang, Jinhee Park, William J Belden, Ronald C Wek, Tracy G Anthony
The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 (-/-), and Atf4 (-/-) mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 (+/-) mice...
April 28, 2017: Scientific Reports
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