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https://www.readbyqxmd.com/read/28715695/new-liver-cancer-biomarkers-pi3k-akt-mtor-pathway-members-and-eukaryotic-translation-initiation-factors
#1
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...
July 14, 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
#2
Daniel Peter, Ramona Weber, Felix Sandmeir, Lara Wohlbold, Sigrun Helms, Praveen Bawankar, Eugene Valkov, Cátia Igreja, Elisa Izaurralde
The eIF4F 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...
July 11, 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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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 initiation factor eIF4G to assess whether this core translation initiation factor has intrinsic sequence preferences that may contribute to preferential translation of specific mRNAs...
May 25, 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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/28428548/antiviral-activities-of-schizonepeta-tenuifolia-briq-against-enterovirus-71-in-vitro-and-in-vivo
#14
Sin-Guang Chen, Mei-Ling Cheng, Kuan-Hsing Chen, Jim-Tong Horng, Ching-Chuan Liu, Shih-Min Wang, Hiroaki Sakurai, Yann-Lii Leu, Shulhn-Der Wang, Hung-Yao Ho
No effective drug is currently available for treatment of enterovirus 71 (EV71) infection. Schizonepeta tenuifolia Briq. (ST) has been used as a herbal constituent of traditional Chinese medicine. We studied whether the aqueous extract of Schizonepeta tenuifolia Briq (STE) has antiviral activity. STE inhibited replication of EV71, as evident by its ability to diminish plaque formation and cytopathic effect induced by EV71, and to inhibit the synthesis of viral RNA and protein. Moreover, daily single-dose STE treatment significantly improved the survival of EV71-infected mice, and ameliorated the symptoms...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28287245/yela-a-putative-dictyostelium-translational-regulator-acts-as-antagonist-of-dif-1-signaling-to-control-cell-type-proportioning
#15
Yoko Yamada, Chris Sugden, Jeffrey G Williams
DIF-1 (differentiation-inducing factor1) is a polyketide produced by Dictyostelium prespore cells which induces initially uncommitted cells to differentiate as prestalk cells. Exposure of cells to DIF-1 causes transitory hypo-phosphorylation of seven serine residues in YelA, a protein with a region of strong homology to the MIF4G domain of the eukaryotic initiation factor eIF4G. Based upon its domain architecture, which in one important aspect closely resembles that of Death-Associated Protein 5 (DAP5), we predict a role in stimulating internal ribosome entry-driven mRNA translation...
2017: International Journal of Developmental Biology
https://www.readbyqxmd.com/read/28287067/translational-control-of-mrnas-by-3-untranslated-region-binding-proteins
#16
Akio Yamashita, Osamu Takeuchi
Eukaryotic gene expression is precisely regulated at all points between transcription and translation. In this review, we focus on translational control mediated by the 3'-untranslated regions (UTRs) of mRNAs. mRNA 3'-UTRs contain cis-acting elements that function in the regulation of protein translation or mRNA decay. Each RNA binding protein that binds to these cis-acting elements regulates mRNA translation via various mechanisms targeting the mRNA cap structure, the eukaryotic initiation factor 4E (eIF4E)-eIF4G complex, ribosomes, and the poly (A) tail...
April 2017: BMB Reports
https://www.readbyqxmd.com/read/28244149/eukaryotic-translation-initiation-factor-2b-beta-eif2b%C3%AE-a-new-class-of-plant-virus-resistance-gene
#17
Jannat Shopan, Haipeng Mou, Lili Zhang, Changtong Zhang, Weiwei Ma, John A Walsh, Zhongyuan Hu, Jinghua Yang, Mingfang Zhang
Recessive resistances to plant viruses in the Potyvirus genus have been found to be based on mutations in the plant eukaryotic translation initiation factors, eIF4E and eIF4G or their isoforms. Here we report that natural, monogenic recessive resistance to the Potyvirus Turnip mosaic virus (TuMV) has been found in a number of mustard (Brassica juncea) accessions. Bulked segregant analysis and sequencing of resistant and susceptible plant lines indicated the resistance is controlled by a single recessive gene, recessive TuMV resistance 03 (retr03), an allele of the eukaryotic translation initiation factor 2B-beta (eIF2Bβ)...
June 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28242763/eukaryotic-translation-initiation-factor-4g-eif4g-coordinates-interactions-with-eif4a-eif4b-and-eif4e-in-binding-and-translation-of-the-barley-yellow-dwarf-virus-3-cap-independent-translation-element-bte
#18
Pei Zhao, Qiao Liu, W Allen Miller, Dixie J Goss
Barley yellow dwarf virus RNA, lacking a 5' cap and a 3' poly(A) tail, contains a cap-independent translation element (BTE) in the 3'-untranslated region that interacts with host translation initiation factor eIF4G. To determine how eIF4G recruits the mRNA, three eIF4G deletion mutants were constructed: (i) eIF4G601-1196, containing amino acids 601-1196, including the putative BTE-binding region, and binding domains for eIF4E, eIF4A, and eIF4B; (ii) eIF4G601-1488, which contains an additional C-terminal eIF4A-binding domain; and (iii) eIF4G742-1196, which lacks the eIF4E-binding site...
April 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28199446/translational-control-in-plant-antiviral-immunity
#19
João Paulo B Machado, Iara P Calil, Anésia A Santos, Elizabeth P B Fontes
Due to the limited coding capacity of viral genomes, plant viruses depend extensively on the host cell machinery to support the viral life cycle and, thereby, interact with a large number of host proteins during infection. Within this context, as plant viruses do not harbor translation-required components, they have developed several strategies to subvert the host protein synthesis machinery to produce rapidly and efficiently the viral proteins. As a countermeasure against infection, plants have evolved defense mechanisms that impair viral infections...
2017: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/28179526/a-sequence-independent-unstructured-internal-ribosome-entry-site-is-responsible-for-internal-expression-of-the-coat-protein-of-turnip-crinkle-virus
#20
Jared May, Philip Johnson, Huma Saleem, Anne E Simon
To maximize the coding potential of viral genomes, internal ribosome entry sites (IRES) can be used to bypass the traditional requirement of a 5' cap and some/all of the associated translation initiation factors. Although viral IRES typically contain higher-order RNA structure, an unstructured sequence of about 84 nucleotides (nt) immediately upstream of the Turnip crinkle virus (TCV) coat protein (CP) open reading frame (ORF) has been found to promote internal expression of the CP from the genomic RNA (gRNA) both in vitro and in vivo An absence of extensive RNA structure was predicted using RNA folding algorithms and confirmed by selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) RNA structure probing...
April 15, 2017: Journal of Virology
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