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https://www.readbyqxmd.com/read/28087669/the-role-of-the-p38-mnk-eif4e-signaling-axis-in-tnf-production-downstream-of-the-nod1-receptor
#1
Mikhail V Pashenkov, Lyudmila S Balyasova, Yulia A Dagil, Boris V Pinegin
Activation of nucleotide-binding oligomerization domain (NOD) 1 and NOD2 by muropeptides triggers a complex transcriptional program in innate immune cells. However, little is known about posttranscriptional regulation of NOD1- and NOD2-dependent responses. When stimulated with a prototypic NOD1 agonist, N-acetylglucosaminyl-N-acetylmuramyl-l-alanyl-d-isoglutamyl-meso-diaminopimelic acid (GM-triDAP), human monocyte-derived macrophages (MDM) produced an order of magnitude more TNF, IL-6, and pro-IL-1β than did monocyte-derived dendritic cells (MDDC), despite similar NOD1 expression, similar cytokine mRNA kinetics, and comparable responses to LPS...
January 13, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28074025/flavivirus-infection-uncouples-translation-suppression-from-cellular-stress-responses
#2
Hanna Roth, Vera Magg, Fabian Uch, Pascal Mutz, Philipp Klein, Katharina Haneke, Volker Lohmann, Ralf Bartenschlager, Oliver T Fackler, Nicolas Locker, Georg Stoecklin, Alessia Ruggieri
: As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with dengue virus (DENV) and Zika virus (ZIKV), two positive-strand RNA flaviviruses...
January 10, 2017: MBio
https://www.readbyqxmd.com/read/28073841/activation-of-eif4e-by-aurora-kinase-a-depicts-a-novel-druggable-axis-in-everolimus-resistant-cancer-cells
#3
Ahmed Katsha, Lihong Wang, Janet Arras, Omar M Omar, Jeffrey A Ecsedy, Abbes Belkhiri, Wael El-Rifai
PURPOSE: In this study, we investigated the role of Aurora kinase A (AURKA) in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus). EXPERIMENTAL DESIGN: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGCs) were used to determine the role of AURKA in activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28068774/mechanism-of-phosphorylation-induced-folding-of-4e-bp2-revealed-by-molecular-dynamics-simulations
#4
Juan Zeng, Fan Jiang, Yun-Dong Wu
Site-specific phosphorylation of an intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can suppress its native function by folding it into a four-stranded β-sheet, but the mechanism of this phosphorylation-induced folding is unclear. In this work, we use all-atom molecular dynamics simulations to investigate both the folded and unfolded states of 4E-BP2 under different phosphorylation states of T37 and T46. The results show that the phosphorylated forms of both T37 and T46 play important roles in stabilizing the folded structure, especially for the β-turns and the sequestered binding motif...
January 10, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28061442/genetic-variants-in-the-tgf%C3%AE-signaling-pathway-influence-expression-of-mirnas-in-colon-and-rectal-normal-mucosa-and-tumor-tissue
#5
Martha L Slattery, Andromahi Trivellas, Andrew J Pellatt, Lila E Mullany, John R Stevens, Roger K Wolff, Jennifer S Herrick
The TGF-β signaling pathway is involved in regulation of cell growth, angiogenesis, and metastasis. We test the hypothesis that genetic variation in the TGF-β signaling pathway alters miRNA expression.We use data from 1188 colorectal cancer cases to evaluate associations between 80 SNPs in 21 genes.Seven variants eIF4E rs12498533, NFκB1 rs230510, TGFB1 rs4803455, TGFBR1 rs1571590 and rs6478974, SMAD3 rs3743343, and RUNX1 rs8134179 were associated with expression level of miRNAs in normal colorectal mucosa...
January 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28059075/deficiency-of-the-eif4e-isoform-ncbp-limits-the-cell-to-cell-movement-of-a-plant-virus-encoding-triple-gene-block-proteins-in-arabidopsis-thaliana
#6
Takuya Keima, Yuka Hagiwara-Komoda, Masayoshi Hashimoto, Yutaro Neriya, Hiroaki Koinuma, Nozomu Iwabuchi, Shuko Nishida, Yasuyuki Yamaji, Shigetou Namba
One of the important antiviral genetic strategies used in crop breeding is recessive resistance. Two eukaryotic translation initiation factor 4E family genes, eIF4E and eIFiso4E, are the most common recessive resistance genes whose absence inhibits infection by plant viruses in Potyviridae, Carmovirus, and Cucumovirus. Here, we show that another eIF4E family gene, nCBP, acts as a novel recessive resistance gene in Arabidopsis thaliana toward plant viruses in Alpha- and Betaflexiviridae. We found that infection by Plantago asiatica mosaic virus (PlAMV), a potexvirus, was delayed in ncbp mutants of A...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28046134/the-triticum-mosaic-virus-5-leader-binds-to-both-eif4g-and-eifiso4g-for-translation
#7
Robyn Roberts, Laura K Mayberry, Karen S Browning, Aurélie M Rakotondrafara
We recently identified a remarkably strong (739 nt-long) IRES-like element in the 5' untranslated region (UTR) of Triticum mosaic virus (TriMV, Potyviridae). Here, we define the components of the cap-binding translation initiation complex that are required for TriMV translation. Using bio-layer interferometry and affinity capture of the native translation apparatus, we reveal that the viral translation element has a ten-fold greater affinity for the large subunit eIF4G/eIFiso4G than to the cap binding protein eIF4E/eIFiso4E...
2017: PloS One
https://www.readbyqxmd.com/read/28043914/bay-1143269-a-novel-mnk1-inhibitor-targets-oncogenic-protein-expression-and-shows-potent-anti-tumor-activity
#8
Susann Santag, Franziska Siegel, Antje M Wengner, Claudia Lange, Ulf Bömer, Knut Eis, Florian Pühler, Philip Lienau, Linda Bergemann, Martin Michels, Franz von Nussbaum, Dominik Mumberg, Kirstin Petersen
The initiation of mRNA translation has received increasing attention as an attractive target for cancer treatment in the recent years. The oncogenic eukaryotic translation initiation factor 4E (eIF4E) is the major substrate of MAP kinase-interacting kinase 1 (MNK1), and it is located at the junction of the cancer-associated PI3K and MAPK pathways. The fact that MNK1 is linked to cell transformation and tumorigenesis renders the kinase a promising target for cancer therapy. We identified a novel small molecule MNK1 inhibitor, BAY 1143269, by high-throughput screening and lead optimization...
December 31, 2016: Cancer Letters
https://www.readbyqxmd.com/read/28042932/novel-adomet-analogues-as-tools-for-enzymatic-transfer-of-photo-crosslinkers-and-capturing-rna-protein-interactions
#9
Fabian Muttach, Florain Mäsing, Armido Studer, Andrea Rentmeister
Elucidation of biomolecular interactions is of utmost importance in biochemistry. Photo-crosslinking offers the possibility to precisely determine RNA-protein interactions. However, despite the inherent specificity of enzymes, approaches for site-specific introduction of photo-crosslinking moieties into nucleic acids are scarce. Methyltransferases in combination with synthetic analogues of their natural cosubstrate S-adenosyl-L-methionine (AdoMet) allow for the post-synthetic site-specific modification of biomolecules...
January 2, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28030835/co-targeting-translation-and-proteasome-rapidly-kills-colon-cancer-cells-with-mutant-ras-raf-via-er-stress
#10
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...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/28030797/galeterone-and-its-analogs-inhibit-mnk-eif4e-axis-synergize-with-gemcitabine-impede-pancreatic-cancer-cell-migration-invasion-and-proliferation-and-inhibit-tumor-growth-in-mice
#11
Andrew K Kwegyir-Afful, Francis N Murigi, Puranik Purushottamachar, Vidya P Ramamurthy, Marlena S Martin, Vincent C O Njar
Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC...
December 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/28003464/nat1-promotes-translation-of-specific-proteins-that-induce-differentiation-of-mouse-embryonic-stem-cells
#12
Hayami Sugiyama, Kazutoshi Takahashi, Takuya Yamamoto, Mio Iwasaki, Megumi Narita, Masahiro Nakamura, Tim A Rand, Masato Nakagawa, Akira Watanabe, Shinya Yamanaka
Novel APOBEC1 target 1 (Nat1) (also known as "p97," "Dap5," and "Eif4g2") is a ubiquitously expressed cytoplasmic protein that is homologous to the C-terminal two thirds of eukaryotic translation initiation factor 4G (Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mES cells) are resistant to differentiation. In the current study, we found that NAT1 and eIF4G1 share many binding proteins, such as the eukaryotic translation initiation factors eIF3 and eIF4A and ribosomal proteins. However, NAT1 did not bind to eIF4E or poly(A)-binding proteins, which are critical for cap-dependent translation initiation...
December 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27994090/a-common-class-of-transcripts-with-5-intron-depletion-distinct-early-coding-sequence-features-and-n1-methyladenosine-modification
#13
Can Cenik, Hon Nian Chua, Guramrit Singh, Abdalla Akef, Michael P Snyder, Alexander F Palazzo, Melissa J Moore, Frederick P Roth
Introns are found in 5' untranslated regions (5'UTRs) for 35% of all human transcripts. These 5'UTR introns are not randomly distributed: genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5'UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5'UTR intron status, we developed a classifier that can predict 5'UTR intron status with >80% accuracy using only sequence features in the early coding region...
December 19, 2016: RNA
https://www.readbyqxmd.com/read/27992464/regulation-of-mrna-translation-is-a-novel-mechanism-for-phthalate-toxicity
#14
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/27986751/a-case-matched-gender-comparison-transcriptomic-screen-identifies-eif4e-and-eif5-as-potential-prognostic-and-tractable-biomarkers-in-male-breast-cancer
#15
Matthew P Humphries, Sree Sundara Rajan, Alastair Droop, Charlotte Suleman, Carmine Carbone, Cecilia Nilsson, Hedieh Honarpisheh, Gábor Cserni, Jo Dent, Laura Fulford, Lee B Jordan, J Louise Jones, Rani Kanthan, Maria Litwiniuk, Anna Di Benedetto, Maria Mottolese, Elena Provenzano, Sami Shousha, Mark Stephens, Rosemary A Walker, Janina Kulka, Ian O Ellis, Margaret Jeffery, Helene H Thygesen, Vera Cappelletti, Maria G Daidone, Ingrid A Hedenfalk, Marie-Louise Fjällskog, Davide Melisi, Lucy Stead, Abeer Shaaban, Valerie Speirs
PURPOSE: Breast cancer (BC) affects both genders, but is understudied in men. Although still rare, male BC is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. EXPERIMENTAL DESIGN: A transcriptomic investigation of male and female BC was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n=477, training; n=220, validation set) and quantified in pre- and post-treatment samples from a male BC patient receiving Everolimus and PI3K/mTOR inhibitor...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27981621/targeting-%C3%AE-catenin-in-hepatocellular-cancers-induced-by-co-expression-of-mutant-%C3%AE-catenin-and-k-ras-in-mice
#16
Junyan Tao, Rong Zhang, Sucha Singh, Minakshi Poddar, Emily Xu, Michael Oertel, Xin Chen, Shanthi Ganesh, Marc Abrams, Satdarshan P Monga
Recently we have shown that co-expression of hMet and mutant-β-catenin using sleeping beauty transposon/transposase leads to HCC in mice that represents around 10% of human HCC. In the current study, we investigate if Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-β-catenin. We also tested therapeutic efficacy of targeting β-catenin in HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with β-catenin mutants (S33Y, S45Y) to yield HCC in mice...
December 16, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27941882/use-of-an-anti-viral-drug-ribavirin-as-an-anti-glioblastoma-therapeutic
#17
F Volpin, J Casaos, J Sesen, A Mangraviti, J Choi, N Gorelick, J Frikeche, T Lott, R Felder, S J Scotland, T S K Eisinger-Mathason, H Brem, B Tyler, N Skuli
The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem-like cells, in vitro...
December 12, 2016: Oncogene
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
#18
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/27932243/inhibition-of-mtor-eif4e-by-anti-viral-drug-ribavirin-effectively-enhances-the-effects-of-paclitaxel-in-oral-tongue-squamous-cell-carcinoma
#19
Dehua Dai, Hujie Chen, Jing Tang, Yi Tang
Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells...
January 22, 2017: Biochemical and Biophysical Research Communications
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
#20
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
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