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https://www.readbyqxmd.com/read/27908244/free-initiation-factors-eif4a-and-eif4b-are-dispensable-for-translation-initiation-on-uncapped-mrnas
#1
P A Sakharov, S Ch Agalarov
The formation of ribosomal 48S initiation complexes at the start AUG codon of uncapped mRNA leader sequences was studied using the methodology of primer extension inhibition (toe-printing). The experiments were performed in the system composed of purified individual components required for translation initiation. The formation of ribosomal 48S initiation complexes at the initiation codon was tested depending on the presence of the initiation factors eIF4F, eIF4A, and eIF4B. Several mRNAs containing short leader sequences lacking the extended secondary structure were studied...
October 2016: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/27892500/four-translation-initiation-pathways-employed-by-the-leaderless-mrna-in-eukaryotes
#2
Kseniya A Akulich, Dmitry E Andreev, Ilya M Terenin, Victoria V Smirnova, Aleksandra S Anisimova, Desislava S Makeeva, Valentina I Arkhipova, Elena A Stolboushkina, Maria B Garber, Maria M Prokofjeva, Pavel V Spirin, Vladimir S Prassolov, Ivan N Shatsky, Sergey E Dmitriev
mRNAs lacking 5' untranslated regions (leaderless mRNAs) are molecular relics of an ancient translation initiation pathway. Nevertheless, they still represent a significant portion of transcriptome in some taxons, including a number of eukaryotic species. In bacteria and archaea, the leaderless mRNAs can bind non-dissociated 70 S ribosomes and initiate translation without protein initiation factors involved. Here we use the Fleeting mRNA Transfection technique (FLERT) to show that translation of a leaderless reporter mRNA is resistant to conditions when eIF2 and eIF4F, two key eukaryotic translation initiation factors, are inactivated in mammalian cells...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27879264/differential-regulation-of-the-melanoma-proteome-by-eif4a1-and-eif4e
#3
Cailin E Joyce, Adrienne G Yanez, Akihiro Mori, Akinori Yoda, Johanna S Carroll, Carl D Novina
Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27858515/eif4b-stimulates-eif4a-atpase-and-unwinding-activities-by-direct-interaction-through-its-7-repeats-region
#4
Alexandra Zoi Andreou, Ulf Harms, Dagmar Klostermeier
Eukaryotic translation initiation starts with binding of the eIF4F complex to the 5'-m7G cap of the mRNA. Recruitment of the 43S pre-initiation complex (PIC), formed by the 40S ribosomal subunit and other translation initiation factors, leads to formation of the 48S PIC that then scans the 5'-untranslated region (5'-UTR) towards the start codon. The eIF4F complex consists of eIF4E, the cap binding protein, eIF4A, a DEAD-box RNA helicase that is believed to unwind secondary structures in the 5'UTR during scanning, and eIF4G, a scaffold protein that binds to both eIF4E and eIF4A...
November 18, 2016: RNA Biology
https://www.readbyqxmd.com/read/27836976/stress-granule-induction-after-brain-ischemia-is-independent-of-eukaryotic-translation-initiation-factor-eif-2%C3%AE-phosphorylation-and-is-correlated-with-a-decrease-in-eif4b-and-eif4e-proteins
#5
María Irene Ayuso, Emma Martínez-Alonso, Ignacio Regidor, Alberto Alcázar
Stress granules (SGs) are cytoplasmic ribonucleoprotein aggregates that are directly connected with the translation-initiation arrest response to cellular stresses. Translation inhibition (TI) is observed in transient brain ischemia, condition which induces persistent TI even after reperfusion, i.e., when blood flow is restored, and causes delayed neuronal death (DND) in selective vulnerable regions. We previously described a connection between TI and DND in the hippocampal cornu ammonis 1 (CA1) in an animal model of transient brain ischemia...
November 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27824302/new-insights-into-the-topology-of-the-scanning-ribosome-during-translation-initiation-lessons-from-viruses
#6
René Toribio, Irene Díaz-López, Iván Ventoso
Location of the translation initiation codon generally requires scanning of the 43S ribosomal preinitiation complex (43S PIC) from the 5' of the mRNA. Associated RNA helicases can facilitate movement of the 43S PIC by removing secondary structure present in the 5' UTR of mRNA, which is required for codon inspection. The canonical RNA-dependent helicase eIF4A is directly involved in this process, as part of the eIF4F complex (eIF4G+eIF4A+eIF4E) that associates first with mRNA and then recruits the 43S PIC to initiate scanning...
November 8, 2016: RNA Biology
https://www.readbyqxmd.com/read/27789529/molecular-pathways-the-eif4f-translation-initiation-complex-new-opportunities-for-cancer-treatment
#7
Helene Malka-Mahieu, Michelle Newman, Laurent Desaubry, Caroline Robert, Stephan Vagner
The eIF4F complex regulates the cap-dependent mRNA translation process. It is becoming increasingly evident that aberrant activity of this complex is observed in many cancers leading to the selective synthesis of proteins involved in tumour growth and metastasis. The selective translation of cellular mRNAs controlled by this complex also contributes to resistance to cancer treatments, and downregulation of the eIF4F complex components can restore sensitivity to various cancer therapies. Here we review the contribution of the eIF4F complex to tumourigenesis with a focus on its role in chemoresistance as well as the promising use of new small molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol and pateamine A...
October 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27763553/4ebp-dependent-signaling-supports-west-nile-virus-growth-and-protein-expression
#8
Katherine D Shives, Aaron R Massey, Nicholas A May, Thomas E Morrison, J David Beckham
West Nile virus (WNV) is a (+) sense, single-stranded RNA virus in the Flavivirus genus. WNV RNA possesses an (m7)GpppNm 5' cap with 2'-O-methylation that mimics host mRNAs preventing innate immune detection and allowing the virus to translate its RNA genome through the utilization of cap-dependent translation initiation effectors in a wide variety of host species. Our prior work established the requirement of the host mammalian target of rapamycin complex 1 (mTORC1) for optimal WNV growth and protein expression; yet, the roles of the downstream effectors of mTORC1 in WNV translation are unknown...
October 18, 2016: Viruses
https://www.readbyqxmd.com/read/27694156/eif4g-an-integrator-of-mrna-metabolism
#9
Satarupa Das, Biswadip Das
The eukaryotic translation initiation factor, eIF4G, plays a key functional role in the initiation of cap-dependent translation by acting as an adapter to nucleate the assembly of eIF4F complex. Together with poly(A)-binding protein and eIF3, eIF4F subsequently triggers the recruitment of 43S ribosomal pre-initiation complex to the messenger RNA template. Since eukaryotes primarily regulate translation at the level of initiation, eIF4G is implicated in the control of eukaryotic gene expression. Remarkably, emerging evidence in Saccharomyces cerevisiae indicates that eIF4G also plays a key role in nuclear mRNA biogenesis and surveillance-a finding that is in agreement with its nuclear distribution...
November 2016: FEMS Yeast Research
https://www.readbyqxmd.com/read/27601676/eif4b-stimulates-translation-of-long-mrnas-with-structured-5-utrs-and-low-closed-loop-potential-but-weak-dependence-on-eif4g
#10
Neelam Dabas Sen, Fujun Zhou, Michael S Harris, Nicholas T Ingolia, Alan G Hinnebusch
DEAD-box RNA helicases eukaryotic translation initiation factor 4A (eIF4A) and Ded1 promote translation by resolving mRNA secondary structures that impede preinitiation complex (PIC) attachment to mRNA or scanning. Eukaryotic translation initiation factor 4B (eIF4B) is a cofactor for eIF4A but also might function independently of eIF4A. Ribosome profiling of mutants lacking eIF4B or with impaired eIF4A or Ded1 activity revealed that eliminating eIF4B reduces the relative translational efficiencies of many more genes than does inactivation of eIF4A, despite comparable reductions in bulk translation, and few genes display unusually strong requirements for both factors...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27533468/synergistic-effects-of-eif4a-and-mek-inhibitors-on-proliferation-of-nras-mutant-melanoma-cell-lines
#11
Hélène Malka-Mahieu, Isabelle Girault, Margot Rubington, Melissa Leriche, Caroline Welsch, Nyam Kamsu-Kom, Qian Zhao, Laurent Desaubry, Stéphan Vagner, Caroline Robert
Activating mutations of the NRAS (neuroblastoma rat sarcoma viral oncogene) protein kinase, present in many cancers, induce a constitutive activation of both the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway and the PI(3)K-AKT-mTOR, pathway. This in turn regulates the formation of the eIF4F eukaryotic translation initiation complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNAs...
September 16, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27494274/coupling-between-the-dead-box-rna-helicases-ded1p-and-eif4a
#12
Zhaofeng Gao, Andrea A Putnam, Heath A Bowers, Ulf-Peter Guenther, Xuan Ye, Audrey Kindsfather, Angela K Hilliker, Eckhard Jankowsky
Eukaryotic translation initiation involves two conserved DEAD-box RNA helicases, eIF4A and Ded1p. Here we show that S. cerevisiae eIF4A and Ded1p directly interact with each other and simultaneously with the scaffolding protein eIF4G. We delineate a comprehensive thermodynamic framework for the interactions between Ded1p, eIF4A, eIF4G, RNA and ATP, which indicates that eIF4A, with and without eIF4G, acts as a modulator for activity and substrate preferences of Ded1p, which is the RNA remodeling unit in all complexes...
2016: ELife
https://www.readbyqxmd.com/read/27430620/amp-kinase-activation-alters-oxidant-induced-stress-granule-assembly-by-modulating-cell-signaling-and-microtubule-organization
#13
Hicham Mahboubi, Antonis E Koromilas, Ursula Stochaj
Eukaryotic cells assemble stress granules (SGs) when translation initiation is inhibited. Different cell signaling pathways regulate SG production. Particularly relevant to this process is 5'-AMP-activated protein kinase (AMPK), which functions as a stress sensor and is transiently activated by adverse physiologic conditions. Here, we dissected the role of AMPK for oxidant-induced SG formation. Our studies identified multiple steps of de novo SG assembly that are controlled by the kinase. Single-cell analyses demonstrated that pharmacological AMPK activation prior to stress exposure changed SG properties, because the granules became more abundant and smaller in size...
October 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27401559/toward-the-mechanism-of-eif4f-mediated-ribosomal-attachment-to-mammalian-capped-mrnas
#14
Parimal Kumar, Christopher U T Hellen, Tatyana V Pestova
Ribosomal attachment to mammalian capped mRNAs is achieved through the cap-eukaryotic initiation factor 4E (eIF4E)-eIF4G-eIF3-40S chain of interactions, but the mechanism by which mRNA enters the mRNA-binding channel of the 40S subunit remains unknown. To investigate this process, we recapitulated initiation on capped mRNAs in vitro using a reconstituted translation system. Formation of initiation complexes at 5'-terminal AUGs was stimulated by the eIF4E-cap interaction and followed "the first AUG" rule, indicating that it did not occur by backward scanning...
July 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27388680/eif4a-rna-helicase-associates-with-cyclin-dependent-protein-kinase-a-in-proliferating-cells-and-is-modulated-by-phosphorylation
#15
Maxwell S Bush, Olivier Pierrat, Candida Nibau, Veronika Mikitova, Tao Zheng, Fiona M K Corke, Konstantinos Vlachonasios, Laura K Mayberry, Karen S Browning, John H Doonan
Eukaryotic initiation factor 4A (eIF4A) is a highly conserved RNA-stimulated ATPase and helicase involved in the initiation of messenger RNA translation. Previously, we found that eIF4A interacts with cyclin-dependent kinase A (CDKA), the plant ortholog of mammalian CDK1. Here, we show that this interaction occurs only in proliferating cells where the two proteins coassociate with 5'-cap-binding protein complexes, eIF4F or the plant-specific eIFiso4F. CDKA phosphorylates eIF4A on a conserved threonine residue (threonine-164) within the RNA-binding motif 1b TPGR...
September 2016: Plant Physiology
https://www.readbyqxmd.com/read/27313212/cell-type-specific-control-of-protein-synthesis-and-proliferation-by-fgf-dependent-signaling-to-the-translation-repressor-4e-bp
#16
Rachel Ruoff, Olga Katsara, Victoria Kolupaeva
Regulation of protein synthesis plays a vital role in posttranscriptional modulation of gene expression. Translational control most commonly targets the initiation of protein synthesis: loading 40S ribosome complexes onto mRNA and AUG start codon recognition. This step is initiated by eukaryotic initiation factor 4E (eIF4E) (the m7GTP cap-binding protein), whose binding to eIF4G (a scaffolding subunit) and eIF4A (an ATP-dependent RNA helicase) leads to assembly of active eIF4F complex. The ability of eIF4E to recognize the cap is prevented by its binding to eIF4E binding protein (4E-BP), which thereby inhibits cap-dependent translation by sequestering eIF4E...
July 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27283511/a-cap-for-every-occasion-alternative-eif4f-complexes
#17
J J David Ho, Stephen Lee
The eukaryotic translation initiation factor 4F (eIF4F) has become essentially synonymous with 5' cap-dependent mRNA translation. Recent studies demonstrate that cells assemble variants of eIF4F to produce adaptive, cap-dependent translatomes during physiological conditions that inhibit eIF4F. These findings challenge us to reassess classical perceptions of cellular translational pathways.
October 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27273304/gprc5a-suppresses-protein-synthesis-at-the-endoplasmic-reticulum-to-prevent-radiation-induced-lung-tumorigenesis
#18
Jian Wang, Alton B Farris, Kaiming Xu, Ping Wang, Xiangming Zhang, Duc M Duong, Hong Yi, Hui-Kuo Shu, Shi-Yong Sun, Ya Wang
GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; however, the underlying mechanism remains unclear. Here we reveal that GPRC5A at the endoplasmic reticulum (ER) membrane suppresses synthesis of the secreted or membrane-bound proteins including a number of oncogenes, the most important one being Egfr. The ER-located GPRC5A disturbs the assembly of the eIF4F-mediated translation initiation complex on the mRNA cap through directly binding to the eIF4F complex with its two middle extracellular loops...
2016: Nature Communications
https://www.readbyqxmd.com/read/27239032/crispr-mediated-drug-target-validation-reveals-selective-pharmacological-inhibition-of-the-rna-helicase-eif4a
#19
Jennifer Chu, Gabriela Galicia-Vázquez, Regina Cencic, John R Mills, Alexandra Katigbak, John A Porco, Jerry Pelletier
Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings...
June 14, 2016: Cell Reports
https://www.readbyqxmd.com/read/27162083/the-role-of-dynamics-and-allostery-in-the-inhibition-of-the-eif4e-eif4g-translation-initiation-factor-complex
#20
Nicola Salvi, Evangelos Papadopoulos, Martin Blackledge, Gerhard Wagner
Lack of regulation of the interaction between the eIF4E/eIF4G subunits of the translation initiation factor complex eIF4F is a hallmark of cancer. The inhibitor 4EGI-1 binds to eIF4E, thereby preventing association with eIF4G through an allosteric mechanism. NMR spectroscopy and MD simulations were used to obtain a mechanistic description of the role of correlated dynamics in this allosteric regulation. We show that binding of 4EGI-1 perturbs native correlated motions and increases correlated fluctuations in part of the eIF4G binding site...
June 13, 2016: Angewandte Chemie
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