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Cap-dependent translation

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https://www.readbyqxmd.com/read/27913822/more-than-just-scanning-the-importance-of-cap-independent-mrna-translation-initiation-for-cellular-stress-response-and-cancer
#1
REVIEW
Rafaela Lacerda, Juliane Menezes, Luísa Romão
The scanning model for eukaryotic mRNA translation initiation states that the small ribosomal subunit, along with initiation factors, binds at the cap structure at the 5' end of the mRNA and scans the 5' untranslated region (5'UTR) until an initiation codon is found. However, under conditions that impair canonical cap-dependent translation, the synthesis of some proteins is kept by alternative mechanisms that are required for cell survival and stress recovery. Alternative modes of translation initiation include cap- and/or scanning-independent mechanisms of ribosomal recruitment...
December 2, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27911187/fxr1a-associated-micrornp-a-driver-of-specialized-non-canonical-translation-in-quiescent-conditions
#2
Syed I A Bukhari, Shobha Vasudevan
Eukaryotic protein synthesis is a multifaceted process that requires coordination of a set of translation factors in a particular cellular state. During normal growth and proliferation, cells generally make their proteome via conventional translation that utilizes canonical translation factors. When faced with environmental stress such as growth factor deprivation, or in response to biological cues such as developmental signals, cells can have stalled canonical translation. In this situation, cells adapt alternative modes of translation to make specific proteins necessary for required biological functions under these distinct conditions...
December 2, 2016: RNA Biology
https://www.readbyqxmd.com/read/27899653/control-of-the-negative-ires-trans-acting-factor-khsrp-by-ubiquitination
#3
Yu-An Kung, Chuan-Tien Hung, Kun-Yi Chien, Shin-Ru Shih
Cells and viruses can utilize internal ribosome entry sites (IRES) to drive translation when cap-dependent translation is inhibited by stress or viral factors. IRES trans-acting factors (ITAFs) are known to participate in such cap-independent translation, but there are gaps in the understanding as to how ITAFs, particularly negative ITAFs, regulate IRES-driven translation. This study found that Lys109, Lys121 and Lys122 represent critical ubiquitination sites for far upstream element-binding protein 2 (KHSRP, also known as KH-type splicing regulatory protein or FBP2), a negative ITAF...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899591/modulation-of-nonsense-mediated-decay-by-rapamycin
#4
Rocio T Martinez-Nunez, Andrew Wallace, Doyle Coyne, Linnea Jansson, Miles Rush, Hanane Ennajdaoui, Sol Katzman, Joanne Bailey, Katrin Deinhardt, Tilman Sanchez-Elsner, Jeremy R Sanford
Rapamycin is a naturally occurring macrolide whose target is at the core of nutrient and stress regulation in a wide range of species. Despite well-established roles as an inhibitor of cap-dependent mRNA translation, relatively little is known about its effects on other modes of RNA processing. Here, we characterize the landscape of rapamycin-induced post-transcriptional gene regulation. Transcriptome analysis of rapamycin-treated cells reveals genome-wide changes in alternative mRNA splicing and pronounced changes in NMD-sensitive isoforms...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27864075/the-natural-compound-silvestrol-is-a-potent-inhibitor-of-ebola-virus-replication
#5
Nadine Biedenkopf, Kerstin Lange-Grünweller, Falk W Schulte, Aileen Weißer, Christin Müller, Dirk Becker, Stephan Becker, Roland K Hartmann, Arnold Grünweller
The DEAD-box RNA helicase eIF4A, which is part of the heterotrimeric translation initiation complex in eukaryotes, is an important novel drug target in cancer research because its helicase activity is required to unwind extended and highly structured 5'-UTRs of several proto-oncogenes. Silvestrol, a natural compound isolated from the plant Aglaia foveolata, is a highly efficient, non-toxic and specific inhibitor of eIF4A. Importantly, 5'-capped viral mRNAs often contain structured 5'-UTRs as well, which may suggest a dependence on eIF4A for their translation by the host protein synthesis machinery...
November 15, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27858515/eif4b-stimulates-eif4a-atpase-and-unwinding-activities-by-direct-interaction-through-its-7-repeats-region
#6
Alexandra Zoi Andreou, Ulf Harms, Dagmar Klostermeier
Eukaryotic translation initiation starts with binding of the eIF4F complex to the 5'-m7G cap of the mRNA. Recruitment of the 43S pre-initiation complex (PIC), formed by the 40S ribosomal subunit and other translation initiation factors, leads to formation of the 48S PIC that then scans the 5'-untranslated region (5'-UTR) towards the start codon. The eIF4F complex consists of eIF4E, the cap binding protein, eIF4A, a DEAD-box RNA helicase that is believed to unwind secondary structures in the 5'UTR during scanning, and eIF4G, a scaffold protein that binds to both eIF4E and eIF4A...
November 18, 2016: RNA Biology
https://www.readbyqxmd.com/read/27853833/a-researcher-s-guide-to-the-galaxy-of-iress
#7
REVIEW
Ilya M Terenin, Victoria V Smirnova, Dmitri E Andreev, Sergey E Dmitriev, Ivan N Shatsky
The idea of internal initiation is frequently exploited to explain the peculiar translation properties or unusual features of some eukaryotic mRNAs. In this review, we summarize the methods and arguments most commonly used to address cases of translation governed by internal ribosome entry sites (IRESs). Frequent mistakes are revealed. We explain why "cap-independent" does not readily mean "IRES-dependent" and why the presence of a long and highly structured 5' untranslated region (5'UTR) or translation under stress conditions cannot be regarded as an argument for appealing to internal initiation...
November 16, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27825141/p73-expression-is-regulated-by-ribosomal-protein-rpl26-through-mrna-translation-and-protein-stability
#8
Min Zhang, Jin Zhang, Wensheng Yan, Xinbin Chen
p73, a p53 family tumor suppressor, is regulated by multiple mechanisms, including transcription and mRNA and protein stability. However, whether p73 expression is regulated via mRNA translation has not been explored. To test this, we examined whether ribosomal protein 26 (RPL26) plays a role in p73 expression. Here, we showed that p73 expression is controlled by RPL26 via protein stability and mRNA translation. To examine whether MDM2 mediates RPL26 to regulate p73 protein stability, we generated multiple MDM2-knockout cell lines by CRISPR-cas9...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27789529/molecular-pathways-the-eif4f-translation-initiation-complex-new-opportunities-for-cancer-treatment
#9
Helene Malka-Mahieu, Michelle Newman, Laurent Desaubry, Caroline Robert, Stephan Vagner
The eIF4F complex regulates the cap-dependent mRNA translation process. It is becoming increasingly evident that aberrant activity of this complex is observed in many cancers leading to the selective synthesis of proteins involved in tumour growth and metastasis. The selective translation of cellular mRNAs controlled by this complex also contributes to resistance to cancer treatments, and downregulation of the eIF4F complex components can restore sensitivity to various cancer therapies. Here we review the contribution of the eIF4F complex to tumourigenesis with a focus on its role in chemoresistance as well as the promising use of new small molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol and pateamine A...
October 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27764673/presynaptic-protein-synthesis-is-required-for-long-term-plasticity-of-gaba-release
#10
Thomas J Younts, Hannah R Monday, Barna Dudok, Matthew E Klein, Bryen A Jordan, István Katona, Pablo E Castillo
Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remain unclear. Here, using paired whole-cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type 1 cannabinoid receptor (CB1)-expressing axons...
October 19, 2016: Neuron
https://www.readbyqxmd.com/read/27763553/4ebp-dependent-signaling-supports-west-nile-virus-growth-and-protein-expression
#11
Katherine D Shives, Aaron R Massey, Nicholas A May, Thomas E Morrison, J David Beckham
West Nile virus (WNV) is a (+) sense, single-stranded RNA virus in the Flavivirus genus. WNV RNA possesses an (m7)GpppNm 5' cap with 2'-O-methylation that mimics host mRNAs preventing innate immune detection and allowing the virus to translate its RNA genome through the utilization of cap-dependent translation initiation effectors in a wide variety of host species. Our prior work established the requirement of the host mammalian target of rapamycin complex 1 (mTORC1) for optimal WNV growth and protein expression; yet, the roles of the downstream effectors of mTORC1 in WNV translation are unknown...
October 18, 2016: Viruses
https://www.readbyqxmd.com/read/27758893/genome-wide-mapping-of-uncapped-and-cleaved-transcripts-reveals-a-role-for-the-nuclear-mrna-cap-binding-complex-in-co-translational-rna-decay-in-arabidopsis
#12
Xiang Yu, Matthew R Willmann, Stephen J Anderson, Brian D Gregory
RNA turnover is necessary for controlling proper mRNA levels post-transcriptionally. In general, RNA degradation is via exoribonucleases that degrade RNA either from the 5' end to the 3' end, such as XRN4, or in the opposite direction by the multi-subunit exosome complex. Here, we use genome-wide mapping of uncapped and cleaved transcripts to reveal the global landscape of co-translational mRNA decay in the Arabidopsis thaliana transcriptome. We found that this process leaves a clear three nucleotide periodicity in open reading frames...
October 7, 2016: Plant Cell
https://www.readbyqxmd.com/read/27756891/c-myc-deregulation-induces-mrna-capping-enzyme-dependency
#13
Olivia Lombardi, Dhaval Varshney, Nicola M Phillips, Victoria H Cowling
c-Myc is a potent driver of many human cancers. Since strategies for directly targeting c-Myc protein have had limited success, upstream regulators and downstream effectors of c-Myc are being investigated as alternatives for therapeutic intervention. c-Myc regulates transcription and formation of the mRNA cap, which is important for transcript maturation and translation. However, the direct mechanism by which c-Myc upregulates mRNA capping is unclear. mRNA cap formation initiates with the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide, catalysed by mRNA capping enzyme (CE/RNGTT)...
October 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27748944/hpip-promotes-gastric-cancer-cell-proliferation-through-activation-of-cap-dependent-translation
#14
Bing Chen, Jin Zhao, Shengbin Zhang, Yonggang Zhang, Zonghai Huang
Cap-dependent translation has an essential role in the control of cell proliferation by initiating the translation of oncogenes involved in the regulation of cell cycle progression, such as cyclin D1, and its deregulation contributes to the development and progression of various types of cancers. Hematopoietic pre-B-cell leukemia transcription factor interacting protein (HPIP) was found to be overexpressed in gastric cancer (GC) tissues compared to normal tissues and to promote GC growth in vitro and in vivo...
October 11, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27729194/vcp-inhibitors-induce-endoplasmic-reticulum-stress-cause%C3%A2-cell-cycle-arrest-trigger-caspase-mediated-cell-death%C3%A2-and-synergistically-kill-ovarian-cancer-cells-in-combination-with-salubrinal
#15
Prabhakar Bastola, Lisa Neums, Frank J Schoenen, Jeremy Chien
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
September 28, 2016: Molecular Oncology
https://www.readbyqxmd.com/read/27713501/in-vivo-analysis-of-internal-ribosome-entry-at-the-hairless-locus-by-genome-engineering-in-drosophila
#16
Thomas K Smylla, Anette Preiss, Dieter Maier
Cell communication in metazoans requires the highly conserved Notch signaling pathway, which is subjected to strict regulation of both activation and silencing. In Drosophila melanogaster, silencing involves the assembly of a repressor complex by Hairless (H) on Notch target gene promoters. We previously found an in-frame internal ribosome entry site in the full length H transcript resulting in two H protein isoforms (H(p120) and H(p150)). Hence, H may repress Notch signalling activity in situations where cap-dependent translation is inhibited...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27712623/viral-and-cellular-mrna-translation-in-coronavirus-infected-cells
#17
K Nakagawa, K G Lokugamage, S Makino
Coronaviruses have large positive-strand RNA genomes that are 5' capped and 3' polyadenylated. The 5'-terminal two-thirds of the genome contain two open reading frames (ORFs), 1a and 1b, that together make up the viral replicase gene and encode two large polyproteins that are processed by viral proteases into 15-16 nonstructural proteins, most of them being involved in viral RNA synthesis. ORFs located in the 3'-terminal one-third of the genome encode structural and accessory proteins and are expressed from a set of 5' leader-containing subgenomic mRNAs that are synthesized by a process called discontinuous transcription...
2016: Advances in Virus Research
https://www.readbyqxmd.com/read/27699901/model-of-the-delayed-translation-of-cyclin-b-maternal-mrna-after-sea-urchin-fertilization
#18
Vincent Picard, Odile Mulner-Lorillon, Jérémie Bourdon, Julia Morales, Patrick Cormier, Anne Siegel, Robert Bellé
Sea urchin eggs exhibit a cap-dependent increase in protein synthesis within minutes after fertilization. This rise in protein synthesis occurs at a constant rate for a great number of proteins translated from the different available mRNAs. Surprisingly, we found that cyclin B, a major cell-cycle regulator, follows a synthesis pattern that is distinct from the global protein population, so we developed a mathematical model to analyze this dissimilarity in biosynthesis kinetic patterns. The model includes two pathways for cyclin B mRNA entry into the translational machinery: one from immediately available mRNA (mRNAcyclinB) and one from mRNA activated solely after fertilization (XXmRNAcyclinB)...
October 4, 2016: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/27696794/increased-activity-of-chondrocyte-translational-apparatus-accompanies-osteoarthritis
#19
Olga Katsara, Mukundan Attur, Rachel Ruoff, Steven B Abramson, Victoria Kolupaeva
Objectives Degeneration of articular cartilage is central to OA pathology; however, the molecular mechanisms leading to these irreversible changes are still poorly understood. Here, we investigated how changes in the chondrocyte translational apparatus may contribute to the pathology of OA. Methods Normal and OA human knee cartilage was used to analyze the activity of different components of the translational machinery. Chondrocytes isolated from lesional and non-lesional areas of OA cartilage were used to estimate relative rate of protein synthesis by metabolic labeling...
October 1, 2016: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/27694156/eif4g-an-integrator-of-mrna-metabolism
#20
Satarupa Das, Biswadip Das
The eukaryotic translation initiation factor, eIF4G, plays a key functional role in the initiation of cap-dependent translation by acting as an adapter to nucleate the assembly of eIF4F complex. Together with poly(A)-binding protein and eIF3, eIF4F subsequently triggers the recruitment of 43S ribosomal pre-initiation complex to the messenger RNA template. Since eukaryotes primarily regulate translation at the level of initiation, eIF4G is implicated in the control of eukaryotic gene expression. Remarkably, emerging evidence in Saccharomyces cerevisiae indicates that eIF4G also plays a key role in nuclear mRNA biogenesis and surveillance-a finding that is in agreement with its nuclear distribution...
November 2016: FEMS Yeast Research
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