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https://www.readbyqxmd.com/read/28843814/interaction-of-2a-proteinase-of-human-rhinovirus-genetic-group-a-with-eif4e-is-required-for-eif4g-cleavage-during-infection
#1
Martina Aumayr, Anna Schrempf, Öykü Üzülmez, Karin M Olek, Tim Skern
In enteroviruses, the inhibition of protein synthesis from capped host cell mRNA is catalyzed by the virally encoded 2A proteinase (2A(pro)), which cleaves eukaryotic initiation factors (eIF) 4GI and 4GII. Despite much investigation, the exact mechanism of 2A(pro) cleavage remains however unclear. Here, we identify the domains responsible for the eIF4E/HRV2 2A(pro) interaction using molecular modelling and describe mutations that impair this interaction and delay in vitro cleavage of eIF4G isoforms. Furthermore, we produced HRV1A viruses bearing the mutation L17R, Y32A or Y86A in the 2A(pro) sequence...
August 24, 2017: Virology
https://www.readbyqxmd.com/read/28827335/cellular-cap-binding-protein-eif4e-promotes-picornavirus-genome-restructuring-and-translation
#2
Brian C Avanzino, Gabriele Fuchs, Christopher S Fraser
Picornaviruses use internal ribosome entry sites (IRESs) to translate their genomes into protein. A typical feature of these IRESs is their ability to bind directly to the eukaryotic initiation factor (eIF) 4G component of the eIF4F cap-binding complex. Remarkably, the hepatitis A virus (HAV) IRES requires eIF4E for its translation, but no mechanism has been proposed to explain this. Here we demonstrate that eIF4E regulates HAV IRES-mediated translation by two distinct mechanisms. First, eIF4E binding to eIF4G generates a high-affinity binding conformation of the eIF4F complex for the IRES...
August 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28801366/fullerenes-may-cause-eif-mediated-perturbation-in-translational-machinery-evidence-from-in-silico-analysis
#3
Sumbul Firdaus, Anupam Dhasmana, Mohd Wahid, Arshad Jawed, Raju K Mandal, Sajad A Dar, Mohammed Y Areeshi, Mohtashim Lohani, Shafiul Haque
GOALS: Fullerenes have tremendous potential for human biological studies which may further lead to their therapeutic applications. Hence, it has become necessary to explore the possibility of their interference with various important cellular processes. The current study was designed to explore how the presence of fullerenes can affect the binding of DNA with different enzymes and factors involved in transcription and translation process. METHODS: Various bioinformatics approaches and software programs were used to study the effect of fullerenes on the binding pattern of DNA with different enzymes and factors involved in transcription and translation process...
August 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/28757063/atp-competitive-marine-derived-natural-products-that-target-the-dead-box-helicase-eif4a
#4
Joseph Tillotson, Magdalena Kedzior, Larissa Guimarães, Alison B Ross, Tara L Peters, Andrew J Ambrose, Cody J Schmidlin, Donna D Zhang, Letícia V Costa-Lotufo, Abimael D Rodríguez, Jonathan H Schatz, Eli Chapman
Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies...
September 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28755203/micrornas-recruit-eif4e2-to-repress-translation-of-target-mrnas
#5
Shaohong Chen, Guangxia Gao
MicroRNAs (miRNAs) recruit the RNA-induced silencing complex (RISC) to repress the translation of target mRNAs. While the 5' 7-methylguanosine cap of target mRNAs has been well known to be important for miRNA repression, the underlying mechanism is not clear. Here we show that TNRC6A interacts with eIF4E2, a homologue of eIF4E that can bind to the cap but cannot interact with eIF4G to initiate translation, to inhibit the translation of target mRNAs. Downregulation of eIF4E2 relieved miRNA repression of reporter expression...
July 28, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28746394/effects-of-oxidative-and-thermal-stresses-on-stress-granule-formation-in-human-induced-pluripotent-stem-cells
#6
Freshteh Palangi, Samson M Samuel, I Richard Thompson, Chris R Triggle, Mohamed M Emara
Stress Granules (SGs) are dynamic ribonucleoprotein aggregates, which have been observed in cells subjected to environmental stresses, such as oxidative stress and heat shock (HS). Although pluripotent stem cells (PSCs) are highly sensitive to oxidative stress, the role of SGs in regulating PSC self-renewal and differentiation has not been fully elucidated. Here we found that sodium arsenite (SA) and HS, but not hydrogen peroxide (H2O2), induce SG formation in human induced (hi) PSCs. Particularly, we found that these granules contain the well-known SG proteins (G3BP, TIAR, eIF4E, eIF4A, eIF3B, eIF4G, and PABP), were found in juxtaposition to processing bodies (PBs), and were disassembled after the removal of the stress...
2017: PloS One
https://www.readbyqxmd.com/read/28744224/downregulated-translation-initiation-signaling-predisposes-low-birth-weight-neonatal-pigs-to-slower-rates-of-muscle-protein-synthesis
#7
Ying Chen, Sydney R McCauley, Sally E Johnson, Robert P Rhoads, Samer W El-Kadi
Low-birth-weight (LBWT) neonates experience restricted muscle growth in their perinatal life. Our aim was to investigate the mechanisms that contribute to slower skeletal muscle growth of LBWT neonatal pigs. Twenty-four 1-day old male LBWT (816 ± 55 g) and normal-birth-weight (NBWT; 1,642 ± 55 g) littermates (n = 12) were euthanized to collect blood and longissimus dorsi (LD) muscle subsamples. Plasma glucose, insulin, and insulin-like growth factor-I (IGF-I) were lower in LBWT compared with NBWT pigs. Muscle IGF-I mRNA expression were lower in LBWT than NBWT pigs...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28715695/new-liver-cancer-biomarkers-pi3k-akt-mtor-pathway-members-and-eukaryotic-translation-initiation-factors
#8
Nicole Golob-Schwarzl, Stefanie Krassnig, Anna M Toeglhofer, Young Nyun Park, Margit Gogg-Kamerer, Klemens Vierlinger, Fabian Schröder, Hyungjn Rhee, Rudolf Schicho, Peter Fickert, Johannes Haybaeck
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The initiation of protein translation is an important rate-limiting step in eukaryotes and is crucial in many viral infections. Eukaryotic translation initiation factors (eIFs) are involved in the initiation step of protein translation and are linked to the phosphatidylinositol-3-kinases PI3K/AKT/mTOR pathway. Therefore we aimed to investigate a potential role of eIFs in HCC. We herein report on the immunohistochemical expression of the various eIF subunits in 235 cases of virus-related human HCC...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28698298/gigyf1-2-proteins-use-auxiliary-sequences-to-selectively-bind-to-4ehp-and-repress-target-mrna-expression
#9
Daniel Peter, Ramona Weber, Felix Sandmeir, Lara Wohlbold, Sigrun Helms, Praveen Bawankar, Eugene Valkov, Cátia Igreja, Elisa Izaurralde
The eIF4E homologous protein (4EHP) is thought to repress translation by competing with eIF4E for binding to the 5' cap structure of specific mRNAs to which it is recruited through interactions with various proteins, including the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins 1 and 2 (GIGYF1/2). Despite its similarity to eIF4E, 4EHP does not interact with eIF4G and therefore fails to initiate translation. In contrast to eIF4G, GIGYF1/2 bind selectively to 4EHP but not eIF4E. Here, we present crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP, which reveal the molecular basis for the selectivity of the GIGYF1/2 proteins for 4EHP...
June 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28610844/overexpression-of-eif4f-components-in-meningiomas-and-suppression-of-meningioma-cell-growth-by-inhibiting-translation-initiation
#10
Janet L Oblinger, Sarah S Burns, Jie Huang, Li Pan, Yulin Ren, Rulong Shen, A Douglas Kinghorn, D Bradley Welling, Long-Sheng Chang
Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation...
June 10, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28599480/downregulation-of-eif4g-by-microrna-503-enhances-drug-sensitivity-of-mcf-7-adr-cells-through-suppressing-the-expression-of-abc-transport-proteins
#11
Xia Pan, Xiaoyan Yang, Jinglei Zang, Si Zhang, Nan Huang, Xinxin Guan, Jianhua Zhang, Zhihui Wang, Xi Li, Xiaoyong Lei
Overexpression of adenosine triphosphate-binding cassette (ABC) transport protein is emerging as a critical contributor to anticancer drug resistance. The eukaryotic translation initiation factor (eIF) 4F complex, the key modulator of mRNA translation, is regulated by the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway in anticancer drug-resistant tumors. The present study demonstrated the roles of ABC translation protein alterations in the acquisition of the Adriamycin (ADM)-resistant phenotype of MCF-7 human breast cells...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28589219/-1-h-13-c-and-15-n-backbone-chemical-shift-assignments-of-4e-bp144-87-and-4e-bp144-87-bound-to-eif4e
#12
Naotaka Sekiyama, Andras Boeszoermenyi, Haribabu Arthanari, Gerhard Wagner, Mélissa Léger-Abraham
The eukaryotic translational initiation factor 4G (eIF4G) interacts with the cap-binding protein eIF4E through a consensus binding motif, Y(X)4LΦ (where X is any amino acid and Φ is a hydrophobic residue). 4E binding proteins (4E-BPs), which also contain a Y(X)4LΦ motif, regulate the eIF4E/eIF4G interaction. The non- or minimally-phosphorylated form of 4E-BP1 binds eIF4E, preventing eIF4E from interacting with eIF4G, thus inhibiting translation initiation. 4EGI-1, a small molecule inhibitor of the eIF4E/eIF4G interaction that is under investigation as a novel anti-cancer drug, has a dual activity; it disrupts the eIF4E/eIF4G interaction and stabilizes the binding of 4E-BP1 to eIF4E...
June 6, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28577281/acquired-tamoxifen-resistance-in-mcf-7-breast-cancer-cells-requires-hyperactivation-of-eif4f-mediated-translation
#13
Dedra H Fagan, Lynsey M Fettig, Svetlana Avdulov, Heather Beckwith, Mark S Peterson, Yen-Yi Ho, Fan Wang, Vitaly A Polunovsky, Douglas Yee
While selective estrogen receptor modulators, such as tamoxifen, have contributed to increased survival in patients with hormone receptor-positive breast cancer, the development of resistance to these therapies has led to the need to investigate other targetable pathways involved in oncogenic signaling. Approval of the mTOR inhibitor everolimus in the therapy of secondary endocrine resistance demonstrates the validity of this approach. Importantly, mTOR activation regulates eukaryotic messenger RNA translation...
August 2017: Hormones & Cancer
https://www.readbyqxmd.com/read/28559344/viral-and-cellular-mrna-specific-activators-harness-pabp-and-eif4g-to-promote-translation-initiation-downstream-of-cap-binding
#14
Richard W P Smith, Ross C Anderson, Osmany Larralde, Joel W S Smith, Barbara Gorgoni, William A Richardson, Poonam Malik, Sheila V Graham, Nicola K Gray
Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28546148/translation-initiation-factor-eif4g1-preferentially-binds-yeast-transcript-leaders-containing-conserved-oligo-uridine-motifs
#15
Boris Zinshteyn, Maria F Rojas-Duran, Wendy V Gilbert
Translational control of gene expression plays essential roles in cellular stress responses and organismal development by enabling rapid, selective, and localized control of protein production. Translational regulation depends on context-dependent differences in the protein output of mRNAs, but the key mRNA features that distinguish efficiently translated mRNAs are largely unknown. Here, we comprehensively determined the RNA-binding preferences of the eukaryotic initiation factor 4G (eIF4G) to assess whether this core translation initiation factor has intrinsic sequence preferences that may contribute to preferential translation of specific mRNAs...
September 2017: RNA
https://www.readbyqxmd.com/read/28522457/structure-of-eif4e-in-complex-with-an-eif4g-peptide-supports-a-universal-bipartite-binding-mode-for-protein-translation
#16
Manuel Miras, Verónica Truniger, Cristina Silva, Núria Verdaguer, Miguel A Aranda, Jordi Querol-Audí
The association-dissociation of the cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) with eIF4G is a key control step in eukaryotic translation. The paradigm on the eIF4E-eIF4G interaction states that eIF4G binds to the dorsal surface of eIF4E through a single canonical alpha-helical motif, while metazoan eIF4E-binding proteins (m4E-BPs) advantageously compete against eIF4G via bimodal interactions involving this canonical motif and a second noncanonical motif of the eIF4E surface. Metazoan eIF4Gs share this extended binding interface with m4E-BPs, with significant implications on the understanding of translation regulation and the design of therapeutic molecules...
July 2017: Plant Physiology
https://www.readbyqxmd.com/read/28515298/crimean-congo-hemorrhagic-fever-virus-nucleocapsid-protein-augments-mrna-translation
#17
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' untranslated region (UTR) with high affinity. It facilitates the translation of reporter mRNA both in vivo and in vitro with the assistance of the 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...
August 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28461326/eif2%C3%AE-phosphorylation-mediates-il24-induced-apoptosis-through-inhibition-of-translation
#18
Leah Persaud, Xuelin Zhong, Giselle Alvarado, Winchie Do, Jordan Dejoie, Anna Zybtseva, Bertal Huseyin Aktas, Moira Sauane
IL24 is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor-suppressor activities of IL24 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/28452293/separation-of-foot-and-mouth-disease-virus-leader-protein-activities-identification-of-mutants-that-retain-efficient-self-processing-activity-but-poorly-induce-eif4g-cleavage
#19
Su Hua Guan, Graham J Belsham
Foot-and-mouth disease virus is a picornavirus and its RNA genome encodes a large polyprotein. The N-terminal part of this polyprotein is the leader protein, a cysteine protease, termed Lpro. The virus causes the rapid inhibition of host cell cap-dependent protein synthesis within infected cells. This results from the Lpro-dependent cleavage of the cellular translation initiation factor eIF4G. Lpro also releases itself from the virus capsid precursor by cleaving the L/P1 junction. Using site-directed mutagenesis of the Lpro coding sequence, we have investigated the role of 51 separate amino acid residues in the functions of this protein...
April 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28442428/rapamycin-modulation-of-p70-s6-kinase-signaling-inhibits-rift-valley-fever-virus-pathogenesis
#20
Todd M Bell, Virginia Espina, Svetlana Senina, Caitlin Woodson, Ashwini Brahms, Brian Carey, Shih-Chao Lin, Lindsay Lundberg, Chelsea Pinkham, Alan Baer, Claudius Mueller, Elizabeth A Chlipala, Faye Sharman, Cynthia de la Fuente, Lance Liotta, Kylene Kehn-Hall
Despite over 60 years of research on antiviral drugs, very few are FDA approved to treat acute viral infections. Rift Valley fever virus (RVFV), an arthropod borne virus that causes hemorrhagic fever in severe cases, currently lacks effective treatments. Existing as obligate intracellular parasites, viruses have evolved to manipulate host cell signaling pathways to meet their replication needs. Specifically, translation modulation is often necessary for viruses to establish infection in their host. Here we demonstrated phosphorylation of p70 S6 kinase, S6 ribosomal protein, and eIF4G following RVFV infection in vitro through western blot analysis and in a mouse model of infection through reverse phase protein microarrays (RPPA)...
July 2017: Antiviral Research
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