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Cap-dependent translation

Tomoyuki Miyamoto, Nobuhiko Mizuno, Mitsuko Kosaka, Yoko Fujitani, Eiji Ohno, Aiji Ohtsuka
The role of octamer-binding transcription factor 4 (OCT4) in human cancer is still debated. Although many studies have been published on human OCT4, determining which of the findings are accurate or which are false-positives is currently challenging. We thus developed the most reliable method to date for highly specific and comprehensive detection of genuine OCT4-transcript variants without false-positive results. Our results provided clear evidence that the transcripts of OCT4A, OCT4B, OCT4B1 and other novel splicing variants are indeed present in many cancer cell lines, but are rarely detected in normal tissue-derived differentiated cells...
May 17, 2018: Stem Cells
Olga Katsara, Victoria Kolupaeva
Proper control of protein synthesis is vital for tissue homeostasis and its deregulation is characteristic of many disorders including osteoarthritis (OA). The objectives of this work were to analyze and correlate changes in activity of the translation apparatus associated with cartilage degeneration in an animal model of OA. Osteoarthritis was induced surgically in rats by anterior cruciate ligament transection (ACLT). Using a modified Mankin scoring system and analysis of protein expression we demonstrated, that mechanistic target of rapamycin complex 1 (mTORC1)-mediated 4E-BP1 phosphorylation was detected significantly earlier than other mTORC1-mediated modifications, such as p70S6K and ULK1 phosphorylation...
May 14, 2018: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Praveen Kumar Jaiswal, Sweaty Koul, Prakash S T Shanmugam, Hari K Koul
eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset)...
May 10, 2018: Scientific Reports
Václav Vopálenský, Anas Khawaja, Luděk Rožnovský, Jakub Mrázek, Tomáš Mašek, Martin Pospíšek
Hepatitis C virus (HCV) is a single-stranded positive-sense RNA virus from the genus Hepacivirus . The viral genomic +RNA is 9.6 kb long and contains highly structured 5' and 3' untranslated regions (UTRs) and codes for a single large polyprotein, which is co- and post-translationally processed by viral and cellular proteases into at least 11 different polypeptides. Most of the 5' UTR and an initial part of the polyprotein gene are occupied by an internal ribosome entry site (IRES), which mediates cap-independent translation of the viral proteins and allows the virus to overcome cellular antiviral defense based on the overall reduction of the cap-dependent translation initiation...
2018: Frontiers in Microbiology
William C Merrick, Graham D Pavitt
This review summarizes our current understanding of the major pathway for the initiation phase of protein synthesis in eukaryotic cells, with a focus on recent advances. We describe the major scanning or messenger RNA (mRNA) m7 G cap-dependent mechanism, which is a highly coordinated and stepwise regulated process that requires the combined action of at least 12 distinct translation factors with initiator transfer RNA (tRNA), ribosomes, and mRNAs. We limit our review to studies involving either mammalian or budding yeast cells and factors, as these represent the two best-studied experimental systems, and only include a reference to other organisms where particular insight has been gained...
May 7, 2018: Cold Spring Harbor Perspectives in Biology
Luis D Arreola-Peralta, Frida Altamirano-Reyna, Deni M Galindo-González, Jessica G Solis-Anguiano, Enza Lacivita, Marcello Leopoldo, José A Terrón
A decrease in the activation threshold of primary sensory neurons to transient receptor potential V1 (TRPV1) stimulation by serotonin 5-HT7 receptors has been reported but no confirmation if this might translate into facilitation of neurogenic inflammation has been provided. We analysed the modulation of capsaicin (CAP)-induced neurogenic inflammation in the rat hind paw by the selective 5-HT7 receptor agonist, LP-44, and the involvement of calcitonin gen-related peptide (CGRP) in this effect. Animals received intra-plantar injections (30 μl) of vehicle, CAP (0...
May 3, 2018: Peptides
Dhaval Varshney, Olivia Lombardi, Gabriele Schweikert, Sianadh Dunn, Olga Suska, Victoria H Cowling
mRNA cap addition occurs early during RNA Pol II-dependent transcription, facilitating pre-mRNA processing and translation. We report that the mammalian mRNA cap methyltransferase, RNMT-RAM, promotes RNA Pol II transcription independent of mRNA capping and translation. In cells, sublethal suppression of RNMT-RAM reduces RNA Pol II occupancy, net mRNA synthesis, and pre-mRNA levels. Conversely, expression of RNMT-RAM increases transcription independent of cap methyltransferase activity. In isolated nuclei, recombinant RNMT-RAM stimulates transcriptional output; this requires the RAM RNA binding domain...
May 1, 2018: Cell Reports
Nick Arndt, Daniela Ross-Kaschitza, Artyom Kojukhov, Anton A Komar, Michael Altmann
Yeast p20 is a small, acidic protein that binds eIF4E, the cap-binding protein. It has been proposed to affect mRNA translation and degradation, however p20's function as an eIF4E-binding protein (4E-BP) and its physiological significance has not been clearly established. In this paper we present data demonstrating that p20 is capable of binding directly to mRNA due to electrostatic interaction of a stretch of arginine and histidine residues in the protein with negatively charged phosphates in the mRNA backbone...
April 30, 2018: Scientific Reports
Blazej Andrzej Wojtczak, Pawel J Sikorski, Kaja Fac-Dabrowska, Anna Nowicka, Marcin Warminski, Dorota Kubacka, Elzbieta Nowak, Marcin Nowotny, Joanna Kowalska, Jacek Jemielity
The 5' cap consists of 7-methylguanosine (m7G) linked by a 5'-5'-triphosphate bridge to mRNA and acts as the master regu-lator of mRNA turnover and translation initiation in eukaryotes. Cap analogs that influence mRNA translation and turnover (either as small molecules or as part of an RNA transcript) are valuable tools for studying gene expression, which is often also of therapeutic relevance. Here, we synthesized a series of 15 dinucleotide cap (m7GpppG) analogs containing a 5'-phosphorothiolate (5'-PSL) moiety (i...
April 20, 2018: Journal of the American Chemical Society
Héloïse Chassé, Julie Aubert, Sandrine Boulben, Gildas Le Corguillé, Erwan Corre, Patrick Cormier, Julia Morales
Early embryogenesis relies on the translational regulation of maternally stored mRNAs. In sea urchin, fertilization triggers a dramatic rise in translation activity, necessary for the onset of cell division. Here, the full spectrum of the mRNAs translated upon fertilization was investigated by polysome profiling and sequencing. The translatome of the early sea urchin embryo gave a complete picture of the polysomal recruitment dynamics following fertilization. Our results indicate that only a subset of maternal mRNAs were selectively recruited onto polysomes, with over-represented functional categories in the translated set...
April 6, 2018: Nucleic Acids Research
Nikolay E Shirokikh, Thomas Preiss
Gene expression universally relies on protein synthesis, where ribosomes recognize and decode the messenger RNA template by cycling through translation initiation, elongation, and termination phases. All aspects of translation have been studied for decades using the tools of biochemistry and molecular biology available at the time. Here, we focus on the mechanism of translation initiation in eukaryotes, which is remarkably more complex than prokaryotic initiation and is the target of multiple types of regulatory intervention...
April 6, 2018: Wiley Interdisciplinary Reviews. RNA
Yumaine Chong, Natasha Saviuk, Brigitte Pie, Nathan Basisty, Ryan K Quinn, Birgit Schilling, Nahum Sonenberg, Ellis Cooper, A Pejmun Haghighi
Throughout the developing nervous system, considerable synaptic re-organization takes place as postsynaptic neurons extend dendrites and incoming axons refine their synapses, strengthening some and eliminating others. It is well accepted that these processes rely on synaptic activity; however, the mechanisms that lead to this developmental reorganization are not fully understood. Here, we explore the regulation of cap-dependent translation, a mechanism known to play a role in synaptic growth and plasticity...
April 3, 2018: Cell Reports
Cinthia C Amaya Ramirez, Petra Hubbe, Nicolas Mandel, Julien Béthune
Initially identified as a factor involved in tyrosine kinase receptor signaling, Grb10-interacting GYF protein 2 (GIGYF2) has later been shown to interact with the 5' cap-binding protein 4EHP as part of a translation repression complex, and to mediate post-transcriptional repression of tethered reporter mRNAs. A current model proposes that GIGYF2 is indirectly recruited to mRNAs by specific RNA-binding proteins (RBPs) leading to translation repression through its association with 4EHP. Accordingly, we recently observed that GIGYF2 also interacts with the miRNA-induced silencing complex and probably modulates its translation repression activity...
March 15, 2018: Nucleic Acids Research
E Maioli, E Daveri, E Maellaro, F Ietta, L Cresti, G Valacchi
In the past few years, we focused the interest on rottlerin, an old/new natural substance that, over the time, has revealed a number of cellular and molecular targets, all potentially implicated in the fight against cancer. Past and recent literature well demonstrated that rottlerin is an inhibitor of enzymes, transcription factors and signaling molecules that control cancer cell life and death. Although the rottlerin anticancer activity has been mainly ascribed to apoptosis and/or autophagy induction, recent findings unveiled the existence of additional mechanisms of toxicity...
May 1, 2018: Archives of Biochemistry and Biophysics
Benjamin R E Harris, Defeng Wang, Ye Zhang, Marina Ferrari, Aniekan Okon, Margot P Cleary, Carston R Wagner, Da-Qing Yang
The p53 tumor suppressor plays a critical role in protecting normal cells from malignant transformation. Development of small molecules to reactivate p53 in cancer cells has been an area of intense research. We previously identified an internal ribosomal entry site (IRES) within the 5' untranslated region of p53 mRNA that mediates translation of the p53 mRNA independent of cap-dependent translation. Our results also show that in response to DNA damage, cells switch from cap-dependent translation to cap-independent translation of p53 mRNA...
May 15, 2018: Molecular and Cellular Biology
Gesine Behrens, Reinhard Winzen, Nina Rehage, Anneke Dörrie, Monika Barsch, Anne Hoffmann, Jörg Hackermüller, Christopher Tiedje, Vigo Heissmeyer, Helmut Holtmann
The expression of proteins during inflammatory and immune reactions is coordinated by post-transcriptional mechanisms. A particularly strong suppression of protein expression is exerted by a conserved translational silencing element (TSE) identified in the 3' UTR of NFKBIZ mRNA, which is among the targets of the RNA-binding proteins Roquin-1/2 and MCPIP1/Regnase-1. We present evidence that in the context of the TSE MCPIP1, so far known for its endonuclease activity toward mRNAs specified by distinct stem-loop (SL) structures, also suppresses translation...
May 4, 2018: Nucleic Acids Research
Jamie K Moy, Arkady Khoutorsky, Marina N Asiedu, Gregory Dussor, Theodore J Price
Plasticity in dorsal root ganglion (DRG) neurons that promotes pain requires activity-dependent mRNA translation. Protein synthesis inhibitors block the ability of many pain-promoting molecules to enhance excitability in DRG neurons and attenuate behavioral signs of pain plasticity. In line with this, we have recently shown that phosphorylation of the 5' cap-binding protein, eIF4E, plays a pivotal role in plasticity of DRG nociceptors in models of hyperalgesic priming. However, mRNA targets of eIF4E phosphorylation have not been elucidated in the DRG...
2018: Frontiers in Cellular Neuroscience
Fangfang Duan, Hao Wu, Dongwei Jia, Weicheng Wu, Shifang Ren, Lan Wang, Shushu Song, Xinying Guo, Fenglin Liu, Yuanyuan Ruan, Jianxin Gu
BACKGROUND & AIMS: Aberrant oncogenic mRNA translation and protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal receptor for activated C-kinase 1 (RACK1) promoted chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis...
February 15, 2018: Journal of Hepatology
Jyotsna Vinayak, Stefano A Marrella, Rawaa H Hussain, Leonid Rozenfeld, Karine Solomon, Mark A Bayfield
In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3'OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3'OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode...
May 4, 2018: Nucleic Acids Research
Nadezda Dolgikh, Manuela Hugle, Meike Vogler, Simone Fulda
Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS -mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS -mutated RMS cells in vitro and in vivo NRAS - or HRAS -mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS -mutated than RAS wild-type RMS tumors in vivo We identified BCL-2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased...
April 15, 2018: Cancer Research
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