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https://www.readbyqxmd.com/read/28174303/central-regulatory-role-for-sin1-in-interferon-%C3%AE-ifn%C3%AE-signaling-and-generation-of-biological-responses
#1
Barbara Kroczynska, Gavin T Blyth, Robert L Rafidi, Beata Majchrzak-Kita, Lucy Xu, Diana Saleiro, Ewa M Kosciuczuk, Jacek Jemielity, Bing Su, Jessica K Altman, Elizabeth A Eklund, Eleanor H Fish, Leonidas C Platanias
The precise signaling mechanisms by which Type II interferon (IFN) receptors control expression of unique genes to induce biological responses remain to be established. We provide evidence that Sin1, a known element of the mammalian target of rapamycin complex 2 (mTORC2), is required for IFNγ-induced phosphorylation and activation of AKT and that such activation mediates downstream regulation of mTORC1 and its effectors. These events play important roles in the assembly of the translation initiation factor 4F (eIF4F) and mRNA translation of ISGs...
February 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28060265/analysis-of-cap-binding-proteins-in-human-cells-exposed-to-physiological-oxygen-conditions
#2
Sara Timpano, Gaelan Melanson, Sonia L Evagelou, Brianna D Guild, Erin J Specker, James Uniacke
Translational control is a focal point of gene regulation, especially during periods of cellular stress. Cap-dependent translation via the eIF4F complex is by far the most common pathway to initiate protein synthesis in eukaryotic cells, but stress-specific variations of this complex are now emerging. Purifying cap-binding proteins with an affinity resin composed of Agarose-linked m(7)GTP (a 5' mRNA cap analog) is a useful tool to identify factors involved in the regulation of translation initiation. Hypoxia (low oxygen) is a cellular stress encountered during fetal development and tumor progression, and is highly dependent on translation regulation...
December 28, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28030835/co-targeting-translation-and-proteasome-rapidly-kills-colon-cancer-cells-with-mutant-ras-raf-via-er-stress
#3
Xiangyun Li, Mei Li, Hang Ruan, Wei Qiu, Xiang Xu, Lin Zhang, Jian Yu
Colorectal cancers with mutant RAS/RAF are therapy refractory. Deregulated mRNA translation has become an emerging target in cancer treatment. We recently reported that mTOR inhibitors induce apoptosis via ER stress and the extrinsic pathway upon acute inhibition of the eIF4F complex in colon cancer cells and xenografts, while mutant BRAF600E leads to therapeutic resistance via ERK-mediated Mcl-1 stabilization. In this study, we demonstrated that several other translation inhibitors also activate ER stress and the extrinsic apoptotic pathway...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28004147/developing-anti-neoplastic-biotherapeutics-against-eif4f
#4
REVIEW
Jutta Steinberger, Jennifer Chu, Rayelle Itoua Maïga, Katia Sleiman, Jerry Pelletier
Biotherapeutics have revolutionized modern medicine by providing medicines that would not have been possible with small molecules. With respect to cancer therapies, this represents the current sector of the pharmaceutical industry having the largest therapeutic impact, as exemplified by the development of recombinant antibodies and cell-based therapies. In cancer, one of the most common regulatory alterations is the perturbation of translational control. Among these, changes in eukaryotic initiation factor 4F (eIF4F) are associated with tumor initiation, progression, and drug resistance in a number of settings...
December 21, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27992464/regulation-of-mrna-translation-is-a-novel-mechanism-for-phthalate-toxicity
#5
Jun Ling, Zenaida P Lopez-Dee, Colby Cottell, Laura Wolfe, Derek Nye
Phthalates are a group of plasticizers that are widely used in many consumer products and medical devices, thus generating a huge burden to human health. Phthalates have been known to cause a number of developmental and reproductive disorders functioning as endocrine modulators. They are also involved in carcinogenesis with mechanisms less understood. To further understand the molecular mechanisms of phthalate toxicity, in this study we reported a new effect of phthalates on mRNA translation/protein synthesis, a key regulatory step of gene expression...
2016: PloS One
https://www.readbyqxmd.com/read/27941351/anti-cancer-effect-of-cap-translation-inhibitor-4egi-1-in-human-glioma-u87-cells-involvement-of-mitochondrial-dysfunction-and-er-stress
#6
Ming Wu, Chi Zhang, Xue-Jun Li, Qing Liu, Siyi Wanggou
BACKGROUND: Cancer cells are frequently addicted to deregulated oncogenic protein translation that usually arises as a consequence of increased signaling flux from eIF4F activation. The small molecule 4EG-I, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anticancer effects in animal models of human cancers. METHODS: Here, we extensively investigated the anticancer activity of 4EGI-1 in human glioma U87 cells...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27908244/free-initiation-factors-eif4a-and-eif4b-are-dispensable-for-translation-initiation-on-uncapped-mrnas
#7
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
#8
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
#9
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
#10
Alexandra Zoi Andreou, Ulf Harms, Dagmar Klostermeier
Eukaryotic translation initiation starts with binding of the eIF4F complex to the 5'-m(7)G 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) toward 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...
January 2, 2017: 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
#11
María I 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, a condition that 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...
December 30, 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
#12
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...
December 2016: RNA Biology
https://www.readbyqxmd.com/read/27789529/molecular-pathways-the-eif4f-translation-initiation-complex-new-opportunities-for-cancer-treatment
#13
Hélène Malka-Mahieu, Michelle Newman, Laurent Désaubry, Caroline Robert, Stéphan 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 tumor 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 tumorigenesis, 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...
January 1, 2017: 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
#14
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
#15
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
#16
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
#17
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
#18
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...
August 5, 2016: ELife
https://www.readbyqxmd.com/read/27430620/amp-kinase-activation-alters-oxidant-induced-stress-granule-assembly-by-modulating-cell-signaling-and-microtubule-organization
#19
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
#20
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
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