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https://www.readbyqxmd.com/read/28087278/prolyl-trna-synthetase-inhibition-promotes-cell-death-in-sk-mel-2%C3%A2-cells-through-gcn2-atf4-pathway-activation
#1
Takeo Arita, Megumi Morimoto, Yukiko Yamamoto, Hitoshi Miyashita, Satoshi Kitazawa, Takaharu Hirayama, Sou Sakamoto, Kazumasa Miyamoto, Ryutaro Adachi, Misa Iwatani, Takahito Hara
Protein translation is highly activated in cancer tissues through oncogenic mutations and amplifications, and this can support survival and aberrant proliferation. Therefore, blocking translation could be a promising way to block cancer progression. The process of charging a cognate amino acid to tRNA, a crucial step in protein synthesis, is mediated by tRNA synthetases such as prolyl tRNA synthetase (PRS). Interestingly, unlike pan-translation inhibitors, we demonstrated that a novel small molecule PRS inhibitor (T-3861174) induced cell death in several tumor cell lines including SK-MEL-2 without complete suppression of translation...
January 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28067447/importance-of-eif2%C3%AE-phosphorylation-as-a-protective-mechanism-against-heat-stress-in-mouse-male-germ-cells
#2
Jungbin Yoon, Kyosun Park, Deog Su Hwang, Kunsoo Rhee
Mammalian male germ cells are exceptionally labile to heat stress. A temporal arrest of translation is one immediate response to heat, which involves heat-induced phosphorylation of eukaryotic initiation factor 2α (eIF2α) to block the formation of the translational initiation complex. Here, we investigated the protective mechanisms against heat stress in mouse male germ cells. All known eIF2α kinases were expressed in lineage- and developmental stage-specific manners in the testis; noteworthy was the presence of Gcn2 (General control nonderepressible 2 kinase) in spermatocytes of all seminiferous tubules...
January 9, 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28057755/general-control-nonderepressible-2-gcn2-kinase-inhibits-target-of-rapamycin-complex-1-in-response-to-amino-acid-starvation-in-saccharomyces-cerevisiae
#3
Wenjie Yuan, Shuguang Guo, Jiaoqi Gao, Mingming Zhong, Gonghong Yan, Wangmeng Wu, Yapeng Chao, Yu Jiang
In eukaryotic cells two conserved protein kinases Gcn2 and TOR complex 1 (TORC1) couple amino acid conditions to protein translation. Gcn2 functions as an amino acid sensor and is activated by uncharged tRNAs which accumulate when intracellular amino acids are limited. Activated Gcn2 phosphorylates and inhibits eukaryotic initiation factor-2α (eIF2α), resulting in repression of general protein synthesis. Like Gcn2, TORC1 is also involved in sensing amino acid conditions. However, the underlying mechanism remains unclear...
January 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28052287/is-overnight-fasting-before-surgery-too-much-or-not-enough-how-basic-aging-research-can-guide-preoperative-nutritional-recommendations-to-improve-surgical-outcomes-a-mini-review
#4
Alban Longchamp, Eylul Harputlugil, Jean-Marc Corpataux, C Keith Ozaki, James R Mitchell
Dietary restriction (DR) is best known for extending lifespan in experimental model organisms, but also increases resistance to a variety of clinically relevant stressors, including those associated with surgery. Extended periods of DR, lasting months to years, are required for optimal longevity benefits in rodents, but short-term dietary preconditioning (less than 1 week) remarkably protects from acute injury. Here, we discuss recent advances in our understanding of the mechanistic basis of short-term DR and fasting in the context of surgical stress resistance, including upstream amino acid sensing by the GCN2 and mTORC1 pathways, and downstream effector mechanisms including increased insulin-dependent prosurvival signaling and elevated endogenous hydrogen sulfide production...
January 5, 2017: Gerontology
https://www.readbyqxmd.com/read/28007891/general-amino-acid-control-and-14-3-3-proteins-bmh1-2-are-required-for-nitrogen-catabolite-repression-sensitive-regulation-of-gln3-and-gat1-localization
#5
Jennifer J Tate, David Buford, Rajendra Rai, Terrance G Cooper
Nitrogen catabolite repression (NCR), the ability of Saccharomyces cerevisiae to use good nitrogen sources in preference to poor ones, derives from nitrogen-responsive regulation of the GATA family transcription activators Gln3 and Gat1 In nitrogen-replete conditions, the GATA factors are cytoplasmic and NCR-sensitive transcription minimal. When only poor nitrogen sources are available, Gln3 is nuclear, dramatically increasing GATA factor-mediated transcription. This regulation was originally attributed to mechanistic Tor protein kinase complex 1 (mTorC1)-mediated control of Gln3 However, we recently showed that two regulatory systems act cumulatively to maintain cytoplasmic Gln3 sequestration, only one of which is mTorC1...
February 2017: Genetics
https://www.readbyqxmd.com/read/27980059/gcn2-links-protein-synthesis-to-the-actin-cytoskeleton
#6
(no author information available yet)
No abstract text is available yet for this article.
December 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27979906/4e-bp-is-a-target-of-the-gcn2-atf4-pathway-during-drosophila-development-and-aging
#7
Min-Ji Kang, Deepika Vasudevan, Kwonyoon Kang, Kyunggon Kim, Jung-Eun Park, Nan Zhang, Xiaomei Zeng, Thomas A Neubert, Michael T Marr, Hyung Don Ryoo
Reduced amino acid availability attenuates mRNA translation in cells and helps to extend lifespan in model organisms. The amino acid deprivation-activated kinase GCN2 mediates this response in part by phosphorylating eIF2α. In addition, the cap-dependent translational inhibitor 4E-BP is transcriptionally induced to extend lifespan in Drosophila melanogaster, but through an unclear mechanism. Here, we show that GCN2 and its downstream transcription factor, ATF4, mediate 4E-BP induction, and GCN2 is required for lifespan extension in response to dietary restriction of amino acids...
2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/27965097/braf-mutated-cells-activate-gcn2-mediated-integrated-stress-response-as-a-cytoprotective-mechanism-in-response-to-vemurafenib
#8
Ikuko Nagasawa, Kazuhiro Kunimasa, Satomi Tsukahara, Akihiro Tomida
In BRAF-mutated melanoma cells, the BRAF inhibitor, vemurafenib, induces phosphorylation of eukaryotic initiation factor 2α (eIF2α) and subsequent induction of activating transcription factor 4 (ATF4), the central regulation node of the integrated stress response (ISR). While the ISR supports cellular adaptation to various stresses, the role of vemurafenib-triggered ISR has not been fully characterized. Here, we showed that in response to vemurafenib, BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 (GCN2), an eIF2α kinase sensing amino acid levels...
January 22, 2017: Biochemical and Biophysical Research Communications
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
#9
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
#10
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...
February 2017: 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
#11
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 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...
December 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27717342/impact-is-a-gcn2-inhibitor-that-limits-lifespan-in-caenorhabditis-elegans
#12
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
#13
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
#14
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
#15
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
#16
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 General Control Non-derepressible 1 (GCN1) 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 salicylic acid (SA), ultraviolet (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...
January 2017: 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
#17
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
#18
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
#19
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
#20
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
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