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Michael B Lazarus, Rebecca S Levin, Kevan M Shokat
Elongation Factor-2 Kinase (eEF2K) in an unusual mammalian enzyme that has one known substrate, elongation factor-2. It belongs to a class of kinases, called alpha kinases, that has little sequence identity to the >500 conventional protein kinases, but performs the same reaction and has similar catalytic residues. The phosphorylation of eEF2 blocks translation elongation, which is thought to be critical to regulating cellular energy usage. Here we report a system for discovering new substrates of alpha kinases and identify the first new substrates of eEF2K including AMPK and alpha4, and determine a sequence motif for the kinase that shows a requirement for threonine residues as the target of phosphorylation...
October 17, 2016: Cellular Signalling
Camila Rubio-Patiño, Jozef P Bossowski, Elodie Villa, Laura Mondragón, Barbara Zunino, Emma Proïcs, Johanna Chiche, Frédéric Bost, Els Verhoeyen, Jean-Ehrland Ricci
Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food...
September 28, 2016: Oncotarget
Aude De Gassart, Olivier Demaria, Rébecca Panes, Léa Zaffalon, Alexey G Ryazanov, Michel Gilliet, Fabio Martinon
Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2...
October 2016: EMBO Reports
Jean-Marc Billod, Patricia Saenz-Mendez, Anders Blomberg, Leif A Eriksson
The eukaryotic translation Elongation Factor 2 (eEF2) is an essential enzyme in protein synthesis. eEF2 contains a unique modification of a histidine (His699 in yeast; HIS) into diphthamide (DTA), obtained via 3-amino-3-carboxypropyl (ACP) and diphthine (DTI) intermediates in the biosynthetic pathway. This essential and unique modification is also vulnerable, in that it can be efficiently targeted by NAD(+)-dependent ADP-ribosylase toxins, such as diphtheria toxin (DT). However, none of the intermediates in the biosynthesis path is equally vulnerable against the toxins...
September 26, 2016: Journal of Chemical Information and Modeling
Ebru Hacıosmanoğlu, Başak Varol, Bilge Özerman Edis, Muhammet Bektaş
Eukaryotic elongation factor 2 (eEF2) plays an important role in eukaryotic polypeptide chain elongation. Adenosine diphosphate (ADP)-ribosylation is a post-translational modification reaction that catalyzes the transfer of ADP-ribose group to eEF2 and this causes the inhibition of protein synthesis. Indeed, in the absence of diptheria toxin, endogenous ADP-ribosylation can occur. eEF2 is phosphorylated by eEF2 kinase which prevents binding to ribosomes thus inhibiting its activity. Increase in endogenous ADP-ribosylation level approximately 70-75 % was observed in IL-1β treated HUVECs...
August 10, 2016: Cytotechnology
Kristen T Crowell, Jennifer L Steiner, Catherine S Coleman, Charles H Lang
BACKGROUND: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function of mammalian target of rapamycin (mTOR). METHODS: Adult male mice were provided an alcohol-containing liquid diet for 24 weeks or an isonitrogenous isocaloric control diet...
September 2016: Alcoholism, Clinical and Experimental Research
E M Meylan, L Breuillaud, T Seredenina, P J Magistretti, O Halfon, R Luthi-Carter, J-R Cardinaux
Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1(-/-) mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1(-/-) mice...
2016: Translational Psychiatry
Chao Zhang, Xiaojuan Liu, Chi Zhang, Jingjing Li, Wanwan Guo, Daliang Yan, Chen Yang, Jianhua Zhao, Xiang Wu, Jiahai Shi
BACKGROUND: Cardiomyocyte apoptosis after myocardial ischemia reperfusion (MIR) blocks the recovery of cardiac function during revascularization treatment. Protein synthesis mediated by eukaryotic elongation factor 2 (eEF2) is vital for the recovery of MIR. eEF2 promotes peptide elongation without phosphorylation of itself. However, the exact function of eEF2 during MIR is unknown. METHODS: We used suture tie-down of left coronary artery (LCA) to induce MIR in vivo, which was confirmed by electrocardiography and Evan's blue/triphenyltetrazolium chloride double staining...
July 8, 2016: Journal of Cardiology
Tomozumi Takatani, Jun Shirakawa, Michael W Roe, Colin A Leech, Bernhard F Maier, Raghavendra G Mirmira, Rohit N Kulkarni
Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis...
2016: Scientific Reports
Keigo Nakamura, Kazuya Kusama, Rulan Bai, Toshihiro Sakurai, Kazuto Isuzugawa, James D Godkin, Yoshihito Suda, Kazuhiko Imakawa
Biochemical and/or physical communication between the conceptus and the uterine endometrium is required for conceptus implantation to the maternal endometrium, leading to placentation and the establishment of pregnancy. We previously reported that in vitro co-culture system with bovine trophoblast CT-1 cells, primary uterine endometrial epithelial cells (EECs), and uterine flushings (UFs) mimics in vivo conceptus attachment process. To identify molecules in UFs responsible for this change, we first characterized protein contents of UFs from day 17 cyclic (C17) and pregnant (P17) ewes through the use of two dimensional-Polyacrylamide Gel Electrophoresis (2D-PAGE), followed by Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) analysis...
2016: PloS One
Botao Liu, Shu-Bing Qian
The broad impact of translational regulation has emerged explosively in the last few years in part due to the technological advance in genome-wide interrogation of gene expression. During mRNA translation, the majority of actively translating ribosomes exist as polysomes in cells with multiple ribosomes loaded on a single transcript. The importance of the monosome, however, has been less appreciated in translational profiling analysis. Here we report that the monosome fraction isolated by sucrose sedimentation contains a large quantity of inactive ribosomes that do not engage on mRNAs to direct translation...
January 2016: Translation
Robert A McKnight, Christian C Yost, Erin K Zinkhan, Qi Fu, Christopher W Callaway, Camille M Fung
Nutrient deprivation suppresses protein synthesis by blocking peptide elongation. Transcriptional upregulation and activation of eukaryotic elongation factor 2 kinase (eEF2K) blocks peptide elongation by phosphorylating eukaryotic elongation factor 2. Previous studies examining placentas from intrauterine growth restricted (IUGR) newborn infants show decreased eEF2K expression and activity despite chronic nutrient deprivation. However, the effect of IUGR on hepatic eEF2K expression in the fetus is unknown. We, therefore, examined the transcriptional regulation of hepatic eEF2K gene expression in a Sprague-Dawley rat model of IUGR...
August 1, 2016: Physiological Genomics
Mario F Muñoz, Sandro Argüelles, Mercedes Cano, Francesco Marotta, Antonio Ayala
We studied the alterations of Elongation Factor 2 (eEF2) in the pineal gland of aged rats as well as the possible protective role of exogenous melatonin on these changes in young rats treated with cumene hydroperoxide (CH), a compound that promotes lipid peroxidation and inhibits protein synthesis. The study was performed using male Wistar rats of 3 (control), 12 and 24 months and 3 month-old rats treated with CH, melatonin and CH plus melatonin. We found that pineal eEF-2 is affected by aging and CH, these changes being prevented by exogenous melatonin in the case of CH-treated rats...
June 13, 2016: Journal of Cellular Biochemistry
Nour Eissa, Hayam Hussein, Hongxing Wang, Mohammad F Rabbi, Charles N Bernstein, Jean-Eric Ghia
BACKGROUND: Many animal models have been developed to characterize the complexity of colonic inflammation. In dextran sodium sulfate (DSS) experimental colitis in mice the choice of reference genes is critical for accurate quantification of target genes using quantitative real time PCR (RT-qPCR). No studies have addressed the performance of reference genes in mice DSS-experimental colitis. This study aimed to determine the stability of reference genes expression (RGE) in DSS-experimental murine colitis...
2016: PloS One
Hazem Ahmed, Shili Duan, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy, Matthieu Schapira
Protein methylation is a post-translational modification with important roles in transcriptional regulation and other biological processes, but the enzyme-substrate relationship between the 68 known human protein methyltransferases and the thousands of reported methylation sites is poorly understood. Here, we propose a bioinformatic approach that integrates structural, biochemical, cellular, and proteomic data to identify novel cellular substrates of the lysine methyltransferase SMYD2. Of the 14 novel putative SMYD2 substrates identified by our approach, six were confirmed in cells by immunoprecipitation: MAPT, CCAR2, EEF2, NCOA3, STUB1, and UTP14A...
June 3, 2016: Journal of Proteome Research
Priyanka D Abeyrathne, Cha San Koh, Timothy Grant, Nikolaus Grigorieff, Andrei A Korostelev
Internal ribosome entry sites (IRESs) mediate cap-independent translation of viral mRNAs. Using electron cryo-microscopy of a single specimen, we present five ribosome structures formed with the Taura syndrome virus IRES and translocase eEF2•GTP bound with sordarin. The structures suggest a trajectory of IRES translocation, required for translation initiation, and provide an unprecedented view of eEF2 dynamics. The IRES rearranges from extended to bent to extended conformations. This inchworm-like movement is coupled with ribosomal inter-subunit rotation and 40S head swivel...
2016: ELife
Jason Murray, Christos G Savva, Byung-Sik Shin, Thomas E Dever, V Ramakrishnan, Israel S Fernández
Viral mRNA sequences with a type IV IRES are able to initiate translation without any host initiation factors. Initial recruitment of the small ribosomal subunit as well as two translocation steps before the first peptidyl transfer are essential for the initiation of translation by these mRNAs. Using electron cryomicroscopy (cryo-EM) we have structurally characterized at high resolution how the Cricket Paralysis Virus Internal Ribosomal Entry Site (CrPV-IRES) binds the small ribosomal subunit (40S) and the translocation intermediate stabilized by elongation factor 2 (eEF2)...
2016: ELife
Ahmed Moghieb, Helen M Bramlett, Jyotirmoy H Das, Zhihui Yang, Tyler Selig, Richard A Yost, Michael S Wang, W Dalton Dietrich, Kevin K W Wang
Acute spinal cord injury (SCI) is a devastating condition with many consequences and no known effective treatment. Although it is quite easy to diagnose traumatic SCI, the assessment of injury severity and projection of disease progression or recovery are often challenging, as no consensus biomarkers have been clearly identified. Here rats were subjected to experimental moderate or severe thoracic SCI. At 24h and 7d postinjury, spinal cord segment caudal to injury center versus sham samples was harvested and subjected to differential proteomic analysis...
July 2016: Molecular & Cellular Proteomics: MCP
Michelle Kao, Daniel A Columbus, Agus Suryawan, Julia Steinhoff-Wagner, Adriana Hernandez-Garcia, Hanh V Nguyen, Marta L Fiorotto, Teresa A Davis
Many low-birth weight infants are at risk for poor growth due to an inability to achieve adequate protein intake. Administration of the amino acid leucine stimulates protein synthesis in skeletal muscle of neonates. To determine the effects of enteral supplementation of the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) on protein synthesis and the regulation of translation initiation and degradation pathways, overnight-fasted neonatal pigs were studied immediately (F) or fed one of five diets for 24 h: low-protein (LP), high-protein (HP), or LP diet supplemented with 4 (HMB4), 40 (HMB40), or 80 (HMB80) μmol HMB·kg body wt(-1)·day(-1) Cell replication was assessed from nuclear incorporation of BrdU in the longissimus dorsi (LD) muscle and jejunum crypt cells...
June 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
James McKendry, Alberto Pérez-López, Michael McLeod, Dan Luo, Jessica R Dent, Benoit Smeuninx, Jinglei Yu, Angela E Taylor, Andrew Philp, Leigh Breen
What is the central question of this study? Does shorter rest between sets of resistance exercise promote a superior circulating hormonal and acute muscle anabolic response compared with longer rest periods? What is the main finding and its importance? We demonstrate that short rest (1 min) between sets of moderate-intensity, high-volume resistance exercise blunts the acute muscle anabolic response compared with a longer rest period (5 min), despite a superior circulating hormonal milieu. These data have important implications for the development of training regimens to maximize muscle hypertrophy...
July 1, 2016: Experimental Physiology
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