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Cap-dependent translation

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https://www.readbyqxmd.com/read/28934492/concerted-action-of-two-3-cap-independent-translation-enhancers-increases-the-competitive-strength-of-translated-viral-genomes
#1
Zhiyou Du, Olga M Alekhina, Konstantin S Vassilenko, Anne E Simon
Several families of plant viruses evolved cap-independent translation enhancers (3'CITE) in the 3' untranslated regions of their genomic (g)RNAs to compete with ongoing cap-dependent translation of cellular mRNAs. Umbravirus Pea enation mosaic virus (PEMV)2 is the only example where three 3'CITEs enhance translation: the eIF4E-binding Panicum mosaic virus-like translational enhancer (PTE) and ribosome-binding 3' T-shaped structure (TSS) have been found in viruses of different genera, while the ribosome-binding kl-TSS that provides a long-distance interaction with the 5' end is unique...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28931068/erk1-2-signalling-protects-against-apoptosis-following-endoplasmic-reticulum-stress-but-cannot-provide-long-term-protection-against-bax-bak-independent-cell-death
#2
Nicola J Darling, Kathryn Balmanno, Simon J Cook
Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway...
2017: PloS One
https://www.readbyqxmd.com/read/28930151/perk-signal-modulated-protein-translation-promotes-the-survivability-of-dengue-2-virus-infected-mosquito-cells-and-extends-viral-replication
#3
Jiun-Nan Hou, Tien-Huang Chen, Yi-Hsuan Chiang, Jing-Yun Peng, Tsong-Han Yang, Chih-Chieh Cheng, Eny Sofiyatun, Cheng-Hsun Chiu, Chuan Chiang-Ni, Wei-June Chen
Survival of mosquitoes from dengue virus (DENV) infection is a prerequisite of viral transmission to the host. This study aimed to see how mosquito cells can survive the infection during prosperous replication of the virus. In C6/36 cells, global protein translation was shut down after infection by DENV type 2 (DENV2). However, it returned to a normal level when infected cells were treated with an inhibitor of the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway. Based on a 7-Methylguanosine 5'-triphosphate (m7GTP) pull-down assay, the eukaryotic translation initiation factor 4F (eIF4F) complex was also identified in DENV2-infected cells...
September 20, 2017: Viruses
https://www.readbyqxmd.com/read/28922394/sequence-features-of-viral-and-human-internal-ribosome-entry-sites-predictive-of-their-activity
#4
Alexey A Gritsenko, Shira Weingarten-Gabbay, Shani Elias-Kirma, Ronit Nir, Dick de Ridder, Eran Segal
Translation of mRNAs through Internal Ribosome Entry Sites (IRESs) has emerged as a prominent mechanism of cellular and viral initiation. It supports cap-independent translation of select cellular genes under normal conditions, and in conditions when cap-dependent translation is inhibited. IRES structure and sequence are believed to be involved in this process. However due to the small number of IRESs known, there have been no systematic investigations of the determinants of IRES activity. With the recent discovery of thousands of novel IRESs in human and viruses, the next challenge is to decipher the sequence determinants of IRES activity...
September 18, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28904350/tia1-dependent-regulation-of-mrna-subcellular-location-and-translation-controls-p53-expression-in-b-cells
#5
Manuel D Díaz-Muñoz, Vladimir Yu Kiselev, Nicolas Le Novère, Tomaz Curk, Jernej Ule, Martin Turner
Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization...
September 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28858511/anchimerically-activated-protides-as-inhibitors-of-cap-dependent-translation-and-inducers-of-chemosensitization-in-mantle-cell-lymphoma
#6
Aniekan Okon, JingJing Han, Surendra Dawadi, Christos Demosthenous, Courtney C Aldrich, Mamta Gupta, Carston R Wagner
The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester...
September 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28854224/the-5-poly-a-leader-of-poxvirus-mrna-confers-a-translational-advantage-that-can-be-achieved-in-cells-with-impaired-cap-dependent-translation
#7
Pragyesh Dhungel, Shuai Cao, Zhilong Yang
The poly(A) leader at the 5'-untranslated region (5'-UTR) is an unusually striking feature of all poxvirus mRNAs transcribed after viral DNA replication (post-replicative mRNAs). These poly(A) leaders are non-templated and of heterogeneous lengths; and their function during poxvirus infection remains a long-standing question. Here, we discovered that a 5'-poly(A) leader conferred a selective translational advantage to mRNA in poxvirus-infected cells. A constitutive and uninterrupted 5'-poly(A) leader with 12 residues was optimal...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28853972/programmed-cell-death-4-mechanism-of-action-the-model-to-be-updated
#8
Polina N Vikhreva, Svetlana V Kalinichenko, Igor V Korobko
Programmed cell death 4 (Pdcd4) is frequently suppressed in tumors of various origins and its suppression correlates with tumor progression. Pdcd4 inhibits cap-dependent translation from mRNAs with highly structured 5'-regions through interaction with the eukaryotic translation initiation factor 4A (eIF4A) helicase and a target transcript. Decrease in Pdcd4 protein is believed to provide a relief of otherwise suppressed eIF4A-dependent translation of proteins facilitating tumor progression. However, it remains unknown if lowered Pdcd4 levels in cells suffices to cause a relief in translation inhibition through appearance of the Pdcd4-free translation-competent eIF4A protein, or more complex and selective mechanisms are involved...
August 30, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28852129/a-novel-function-of-ciap1-as-a-mediator-of-chip-driven-eif4e-regulation
#9
Tae Woong Seo, Ji Sun Lee, Ye Na Choi, Dar Heum Jeong, Sun Kyung Lee, Soon Ji Yoo
eIF4E is an initiator protein in cap-dependent translation. Its overexpression is linked to tumorigenesis in various human cancers, suggesting that the levels of eIF4E must be under tight control in normal cells. Although several eIF4E regulatory mechanisms have been demonstrated, the intracellular mechanisms controlling eIF4E protein levels remain poorly understood. Here, we report that eIF4E is efficiently regulated by dual mechanisms, both involving human inhibitor of apoptosis family protein cIAP1. cIAP1 itself ubiquitinates eIF4E as an E3 ligase, and interestingly, cIAP1 also functions as a mediator to present eIF4E to another E3 ligase, CHIP...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28837386/crosstalk-between-translation-and-the-aggresome-autophagy-pathway
#10
Yeonkyoung Park, Joori Park, Yoon Ki Kim
Many neurodegenerative disorders feature the presence of misfolded polypeptide-containing intracellular inclusion bodies biochemically and morphologically analogous to cellular aggresomes. However, it is largely unknown how misfolded polypeptides form aggresomes and are eventually cleared by the aggresome-macroautophagy/autophagy pathway, so-called aggrephagy. Our recent study revealed that when the ubiquitin-proteasome system is impaired, the accumulated misfolded polypeptides are selectively recognized and transported to the aggresome by a CED complex...
August 24, 2017: Autophagy
https://www.readbyqxmd.com/read/28827335/cellular-cap-binding-protein-eif4e-promotes-picornavirus-genome-restructuring-and-translation
#11
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/28814241/the-emerging-picture-of-cdk11-genetic-functional-and-medicinal-aspects
#12
Nikolas Ferreira Dos Santos Paparidis, Fernanda Canduri
Cyclin-dependent kinase 11 is a relatively neglected member of the transcriptional CDKs subfamily, despite possibly being the most versatile CDK in this group. Different CDK11 variants are known to play essential roles in major cellular processes as mRNA transcription (CDK11p110), mitosis (CDK11p58), and apoptosis (CDK11p46 and CDK11p60). Each CDK11 species targets a particular set of substrates related to its functional background, but all isoforms originate from the CDC2L gene complex in human chromosome 1p36...
August 14, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28803610/two-distinct-nodes-of-translational-inhibition-in-the-integrated-stress-response
#13
Hyung Don Ryoo, Deepika Vasudevan
The Integrated Stress Response (ISR) refers to a signaling pathway initiated by stress-activated eIF2α kinases. Once activated, the pathway causes attenuation of global mRNA translation while also paradoxically inducing stress response gene expression. A detailed analysis of this pathway has helped us better understand how stressed cells coordinate gene expression at translational and transcriptional levels. The translational attenuation associated with this pathway has been largely attributed to the phosphorylation of the translational initiation factor eIF2α...
August 14, 2017: BMB Reports
https://www.readbyqxmd.com/read/28757063/atp-competitive-marine-derived-natural-products-that-target-the-dead-box-helicase-eif4a
#14
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/28755480/g3bp1-interacts-directly-with-the-fmdv-ires-and-negatively-regulates-translation
#15
Alfonso Galan, Gloria Lozano, David Piñeiro, Encarnacion Martinez-Salas
RNA-protein interactions play a pivotal role in the function of picornavirus internal ribosome entry site (IRES) elements. Here we analysed the impact of Ras GTPase SH3 domain binding protein 1 (G3BP1) in the IRES activity of foot-and-mouth disease virus (FMDV). We found that G3BP1 interacts directly with three distinct sequences of the IRES element using RNA electrophoretic mobility-shift assays. Analysis of the interaction with domain 5 indicated that the G3BP1 binding-site is placed at the single-stranded region although it allows large sequence heterogeneity and the hairpin located upstream of this region enhances retarded complex formation...
July 29, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28745319/the-androgen-receptor-is-a-negative-regulator-of-eif4e-phosphorylation-at-s209-implications-for-the-use-of-mtor-inhibitors-in-advanced-prostate-cancer
#16
L S D'Abronzo, S Bose, M E Crapuchettes, R E Beggs, R L Vinall, C G Tepper, S Siddiqui, M Mudryj, F U Melgoza, B P Durbin-Johnson, R W deVere White, P M Ghosh
The antiandrogen bicalutamide is widely used in the treatment of advanced prostate cancer (PCa) in many countries, but its effect on castration-resistant PCa (CRPC) is limited. We previously showed that resistance to bicalutamide results from activation of mechanistic target of rapamycin (mTOR). Interestingly, clinical trials testing combinations of the mTOR inhibitor RAD001 with bicalutamide were effective in bicalutamide-naïve CRPC patients, but not in bicalutamide-pretreated ones. Here we investigate causes for their difference in response...
July 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28714086/n-glycan-content-modulates-kainate-receptor-functional-properties
#17
Claire G Vernon, Bryan A Copits, Jacob R Stolz, Yomayra F Guzmán, Geoffrey T Swanson
KEY POINTS: Ionotropic glutamate receptor (iGluR) subunits are N-glycosylated at 4-12 sites, and Golgi processing produces mature receptors that contain high-mannose, hybrid and complex oligosaccharides. N-glycosylation is crucial for receptor biogenesis, influences receptor trafficking and provides a binding site for carbohydrate binding proteins. Glycan moieties are large, polar and occasionally charged, and they are attached at sites along iGluRs that position them for involvement in the structural changes underlying gating...
September 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28699639/loss-of-mtorc1-signalling-impairs-%C3%AE-cell-homeostasis-and-insulin-processing
#18
Manuel Blandino-Rosano, Rebecca Barbaresso, Margarita Jimenez-Palomares, Nadejda Bozadjieva, Joao Pedro Werneck-de-Castro, Masayuki Hatanaka, Raghavendra G Mirmira, Nahum Sonenberg, Ming Liu, Markus A Rüegg, Michael N Hall, Ernesto Bernal-Mizrachi
Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKO(f/f)) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation...
July 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28698206/expression-of-pim-kinases-in-reed-sternberg-cells-fosters-immune-privilege-and-tumor-cell-survival-in-hodgkin-lymphoma
#19
Maciej Szydłowski, Monika Prochorec-Sobieszek, Anna Szumera-Cieckiewicz, Edyta Derezinska, Grazyna Hoser, Danuta Wasilewska, Olga Szymanska-Giemza, Ewa Jabłonska, Emilia Białopiotrowicz, Tomasz Sewastianik, Anna Polak, Wojciech Czardybon, Michał Gałezowski, Renata Windak, Jan Maciej Zaucha, Krzysztof Warzocha, Krzysztof Brzózka, Przemysław Juszczynski
Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) express multiple immunoregulatory proteins that shape the cHL microenvironment and allow tumor cells to evade immune surveillance. Expression of certain immunoregulatory proteins is modulated by pro-survival transcription factors, such as NFκB and STATs. Since these factors also induce expression of the oncogenic PIM1/2/3 serine/threonine kinases, and since PIMs modulate transcriptional activity of NFκB and STATs, we hypothesized that these kinases support RS cell survival and foster their immune privilege...
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28674170/the-mnk-eif4e-signaling-axis-contributes-to-injury-induced-nociceptive-plasticity-and-the-development-of-chronic-pain
#20
Jamie K Moy, Arkady Khoutorsky, Marina N Asiedu, Bryan J Black, Jasper L Kuhn, Paulino Barragán-Iglesias, Salim Megat, Michael D Burton, Carolina C Burgos-Vega, Ohannes K Melemedjian, Scott Boitano, Josef Vagner, Christos G Gkogkas, Joseph J Pancrazio, Jeffrey S Mogil, Gregory Dussor, Nahum Sonenberg, Theodore J Price
Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5' cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain...
August 2, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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