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EIF4A

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https://www.readbyqxmd.com/read/27928055/minimum-noise-production-of-translation-factor-eif4g-maps-to-a-mechanistically-determined-optimal-rate-control-window-for-protein-synthesis
#1
Xiang Meng, Helena Firczuk, Paola Pietroni, Richard Westbrook, Estelle Dacheux, Pedro Mendes, John E G McCarthy
Gene expression noise influences organism evolution and fitness. The mechanisms determining the relationship between stochasticity and the functional role of translation machinery components are critical to viability. eIF4G is an essential translation factor that exerts strong control over protein synthesis. We observe an asymmetric, approximately bell-shaped, relationship between the average intracellular abundance of eIF4G and rates of cell population growth and global mRNA translation, with peak rates occurring at normal physiological abundance...
December 7, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27913706/stat1-promotes-kras-colon-tumor-growth-and-susceptibility-to-pharmacological-inhibition-of-translation-initiation-factor-eif4a
#2
Shuo Wang, Cedric Darini, Laurent Désaubry, Antonis E Koromilas
The transcription factor STAT1 displays antitumor functions for certain forms of cancer via immunoregulatory and cell-autonomous pathways. Paradoxically, STAT1 can promote the survival of different tumor types treated with chemotherapeutic drugs through mechanisms that are not clearly defined. Herein, we demonstrate that STAT1 displays prosurvival effects in human KRAS colon tumor cells by regulating pathways that converge on the initiation of mRNA translation. Specifically, STAT1 increases PI3K class IB signaling and promotes the downregulation of the programmed cell death protein 4 (PDCD4), a protein with tumor-suppressive properties...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27908244/free-initiation-factors-eif4a-and-eif4b-are-dispensable-for-translation-initiation-on-uncapped-mrnas
#3
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/27864075/the-natural-compound-silvestrol-is-a-potent-inhibitor-of-ebola-virus-replication
#4
Nadine Biedenkopf, Kerstin Lange-Grünweller, Falk W Schulte, Aileen Weißer, Christin Müller, Dirk Becker, Stephan Becker, Roland K Hartmann, Arnold Grünweller
The DEAD-box RNA helicase eIF4A, which is part of the heterotrimeric translation initiation complex in eukaryotes, is an important novel drug target in cancer research because its helicase activity is required to unwind extended and highly structured 5'-UTRs of several proto-oncogenes. Silvestrol, a natural compound isolated from the plant Aglaia foveolata, is a highly efficient, non-toxic and specific inhibitor of eIF4A. Importantly, 5'-capped viral mRNAs often contain structured 5'-UTRs as well, which may suggest a dependence on eIF4A for their translation by the host protein synthesis machinery...
November 15, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27858515/eif4b-stimulates-eif4a-atpase-and-unwinding-activities-by-direct-interaction-through-its-7-repeats-region
#5
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/27836619/nanolc-ms-coupling-of-liquid-microjunction-microextraction-for-on-tissue-proteomic-analysis
#6
Jusal Quanico, Julien Franck, Tristan Cardon, Eric Leblanc, Maxence Wisztorski, Michel Salzet, Isabelle Fournier
Mass spectrometry (MS)-based microproteomics on localized regions of tissue sections was achieved by direct coupling of liquid microjunction microextraction with a nanoscale liquid chromatography-tandem MS, resulting in the identification of >500 protein groups from a region as small as 250μm in diameter representing only a few hundred of cells. The method was applied on the examination of benign and tumor regions initially defined by imaging mass spectrometry (IMS) analysis of a consecutive high grade serous ovarian tumor tissue section...
November 9, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27824302/new-insights-into-the-topology-of-the-scanning-ribosome-during-translation-initiation-lessons-from-viruses
#7
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/27601676/eif4b-stimulates-translation-of-long-mrnas-with-structured-5-utrs-and-low-closed-loop-potential-but-weak-dependence-on-eif4g
#8
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
#9
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
#10
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/27474115/class-i-and-ii-small-heat-shock-proteins-together-with-hsp101-protect-protein-translation-factors-during-heat-stress
#11
Fionn McLoughlin, Eman Basha, Mary E Fowler, Minsoo Kim, Juliana Bordowitz, Surekha Katiyar-Agarwal, Elizabeth Vierling
The ubiquitous small heat shock proteins (sHSPs) are well documented to act in vitro as molecular chaperones to prevent the irreversible aggregation of heat-sensitive proteins. However, the in vivo activities of sHSPs remain unclear. To investigate the two most abundant classes of plant cytosolic sHSPs (class I [CI] and class II [CII]), RNA interference (RNAi) and overexpression lines were created in Arabidopsis (Arabidopsis thaliana) and shown to have reduced and enhanced tolerance, respectively, to extreme heat stress...
October 2016: Plant Physiology
https://www.readbyqxmd.com/read/27401559/toward-the-mechanism-of-eif4f-mediated-ribosomal-attachment-to-mammalian-capped-mrnas
#12
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/27392023/evaluation-of-reference-genes-for-reverse-transcription-quantitative-pcr-studies-of-physiological-responses-in-the-ghost-moth-thitarodes-armoricanus-lepidoptera-hepialidae
#13
Guiqing Liu, Xuehong Qiu, Li Cao, Yi Zhang, Zubing Zhan, Richou Han
Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is the sensitive method to quantify the expression levels of target genes on the basis of endogenous control. An appropriate reference gene set for normalization is essential for reliable results. The ghost moth, Thitarodes armoricanus, a host species of a medicinal fungus, Ophiocordyceps sinensis, is an economically important member of the Lepidoptera. Recent studies have focused on the mechanism of adaptation of this species to its high-altitude environment and host immune response to O...
2016: PloS One
https://www.readbyqxmd.com/read/27388680/eif4a-rna-helicase-associates-with-cyclin-dependent-protein-kinase-a-in-proliferating-cells-and-is-modulated-by-phosphorylation
#14
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/27354062/coordinated-regulation-of-cap-dependent-translation-and-microrna-function-by-convergent-signaling-pathways
#15
Scott H Olejniczak, Gaspare La Rocca, Megan R Radler, Shawn M Egan, Qing Xiang, Ralph Garippa, Craig B Thompson
Cell growth and proliferation require the coordinated activation of many cellular processes, including cap-dependent mRNA translation. MicroRNAs oppose cap-dependent translation and set thresholds for expression of target proteins. Emerging data suggest that microRNA function is enhanced by cellular activation due in part to induction of the RNA-induced silencing complex (RISC) scaffold protein GW182. In the current study, we demonstrate that increased expression of GW182 in activated or transformed immune cells results from effects of phosphoinositol 3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) and Jak-Stat-Pim signaling on the translation of GW182 mRNA...
September 15, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27335721/hippuristanol-a-potent-steroid-inhibitor-of-eukaryotic-initiation-factor-4a
#16
REVIEW
Regina Cencic, Jerry Pelletier
Protein synthesis and its regulatory signaling pathways play essential roles in the initiation and maintenance of the cancer phenotype. Insight obtained over the last 3 decades on the mechanisms regulating translation in normal and transformed cells have revealed that perturbed control in cancer cells may offer an Achilles' heel for the development of novel anti-neoplastic agents. Several small molecule inhibitors have been identified and characterized that target translation initiation - more specifically, the rate-limiting step where ribosomes are recruited to mRNA templates...
January 2016: Translation
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
#17
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/27309803/rocaglates-convert-dead-box-protein-eif4a-into-a-sequence-selective-translational-repressor
#18
Shintaro Iwasaki, Stephen N Floor, Nicholas T Ingolia
Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumour cells and repress translation of specific messenger RNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its messenger RNA selectivity is proposed to reflect highly structured 5' untranslated regions that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA...
June 23, 2016: Nature
https://www.readbyqxmd.com/read/27297394/microfilariae-of-brugia-malayi-inhibit-the-mtor-pathway-and-induce-autophagy-in-human-dendritic-cells
#19
Prakash Babu Narasimhan, Sasisekhar Bennuru, Zhaojing Meng, Rachel N Cotton, Kathleen R Elliott, Sundar Ganesan, Renee McDonald-Fleming, Timothy D Veenstra, Thomas B Nutman, Roshanak Tolouei Semnani
Immune modulation is a hallmark of patent filarial infection, including suppression of antigen-presenting cell function and downmodulation of filarial antigen-specific T cell responses. The mammalian target of rapamycin (mTOR) signaling pathway has been implicated in immune regulation, not only by suppressing T cell responses but also by regulating autophagy (through mTOR sensing amino acid availability). Global proteomic analysis (liquid chromatography-tandem mass spectrometry) of microfilaria (mf)-exposed monocyte-derived dendritic cells (DC) indicated that multiple components of the mTOR signaling pathway, including mTOR, eIF4A, and eIF4E, are downregulated by mf, suggesting that mf target this pathway for immune modulation in DC...
September 2016: Infection and Immunity
https://www.readbyqxmd.com/read/27282465/shigella-flexneri-modulates-stress-granule-composition-and-inhibits-stress-granule-aggregation
#20
Pascale Vonaesch, François-Xavier Campbell-Valois, Alexandre Dufour, Philippe J Sansonetti, Pamela Schnupf
Invasion and multiplication of the facultative, cytosolic, enteropathogen Shigella flexneri within the colonic epithelial lining leads to an acute inflammatory response, fever and diarrhea. During the inflammatory process, infected cells are subjected to numerous stresses including heat, oxidative stress and genotoxic stress. The evolutionarily conserved pathway of cellular stress management is the formation of stress granules that store translationally inactive cellular mRNAs and interfere with cellular signalling pathways by sequestering signalling components...
July 2016: Cellular Microbiology
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