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https://www.readbyqxmd.com/read/28515298/crimean-congo-hemorrhagic-fever-virus-nucleocapsid-protein-augments-mrna-translation
#1
Subbiah Jeeva, Erdong Cheng, Safder S Ganaie, Mohammad A Mir
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne nairovirus of the Bunyaviridae family, causing severe illness with high mortality rates in humans. Here we demonstrate that CCHFV nucleocapsid protein (CCHFV-NP) augments mRNA translation. CCHFV-NP binds to the viral mRNA 5' UTR with high affinity. It facilitates the translation of reporter mRNA both in vivo and in vitro with the assistance of viral mRNA 5' UTR. CCHFV-NP equally favors the translation of both capped and uncapped mRNAs, demonstrating the independence of this translation strategy on the 5' cap...
May 17, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28461326/eif2%C3%AE-phosphorylation-mediates-il24-induced-apoptosis-through-inhibition-of-translation
#2
Leah Persaud, Xuelin Zhong, Giselle Alvarado, Winchie Do, Jordan Dejoie, Anna Zybtseva, Bertal H Aktas, Moira Sauane
Interleukin 24 (IL-24) is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. Supra-physiologic activation and/or overexpression of translation initiation factors are implicated in the initiation and progression of cancer animal models as well as a subset of human cancers. Activation and/or overexpression of translation initiation factors correlate with aggressiveness of cancer and poor prognosis...
May 1, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28450740/the-centrosomal-ofd1-protein-interacts-with-the-translation-machinery-and-regulates-the-synthesis-of-specific-targets
#3
Daniela Iaconis, Maria Monti, Mario Renda, Arianne van Koppen, Roberta Tammaro, Marco Chiaravalli, Flora Cozzolino, Paola Pignata, Claudia Crina, Piero Pucci, Alessandra Boletta, Vincenzo Belcastro, Rachel H Giles, Enrico Maria Surace, Simone Gallo, Mario Pende, Brunella Franco
Protein synthesis is traditionally associated with specific cytoplasmic compartments. We now show that OFD1, a centrosomal/basal body protein, interacts with components of the Preinitiation complex of translation (PIC) and of the eukaryotic Initiation Factor (eIF)4F complex and modulates the translation of specific mRNA targets in the kidney. We demonstrate that OFD1 cooperates with the mRNA binding protein Bicc1 to functionally control the protein synthesis machinery at the centrosome where also the PIC and eIF4F components were shown to localize in mammalian cells...
April 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28379136/la-related-protein-1-larp1-binds-the-mrna-cap-blocking-eif4f-assembly-on-top-mrnas
#4
Roni M Lahr, Bruno D Fonseca, Gabrielle E Ciotti, Hiba A Al-Ashtal, Jian-Jun Jia, Marius R Niklaus, Sarah P Blagden, Tommy Alain, Andrea J Berman
The 5'terminal oligopyrimidine (5'TOP) motif is a cis-regulatory RNA element located immediately downstream of the 7-methylguanosine [m(7)G] cap of TOP mRNAs, which encode ribosomal proteins and translation factors. In eukaryotes, this motif coordinates the synchronous and stoichiometric expression of the protein components of the translation machinery. La-related protein 1 (LARP1) binds TOP mRNAs, regulating their stability and translation. We present crystal structures of the human LARP1 DM15 region in complex with a 5'TOP motif, a cap analog (m(7)GTP), and a capped cytidine (m(7)GpppC), resolved to 2...
April 7, 2017: ELife
https://www.readbyqxmd.com/read/28251928/structure-of-human-ifit1-with-capped-rna-reveals-adaptable-mrna-binding-and-mechanisms-for-sensing-n1-and-n2-ribose-2-o-methylations
#5
Yazan M Abbas, Beatrice Theres Laudenbach, Saúl Martínez-Montero, Regina Cencic, Matthias Habjan, Andreas Pichlmair, Masad J Damha, Jerry Pelletier, Bhushan Nagar
IFIT1 (IFN-induced protein with tetratricopeptide repeats-1) is an effector of the host innate immune antiviral response that prevents propagation of virus infection by selectively inhibiting translation of viral mRNA. It relies on its ability to compete with the translation initiation factor eIF4F to specifically recognize foreign capped mRNAs, while remaining inactive against host mRNAs marked by ribose 2'-O methylation at the first cap-proximal nucleotide (N1). We report here several crystal structures of RNA-bound human IFIT1, including a 1...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28174303/central-regulatory-role-for-sin1-in-interferon-%C3%AE-ifn%C3%AE-signaling-and-generation-of-biological-responses
#6
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 N Fish, Leonidas C Platanias
The precise signaling mechanisms by which type II 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 eukaryotic translation initiation factor 4F (eIF4F) and mRNA translation of IFN-stimulated genes...
March 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28060265/analysis-of-cap-binding-proteins-in-human-cells-exposed-to-physiological-oxygen-conditions
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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...
February 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/27858515/eif4b-stimulates-eif4a-atpase-and-unwinding-activities-by-direct-interaction-through-its-7-repeats-region
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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