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Cap-dependent translation

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https://www.readbyqxmd.com/read/28814241/the-emerging-picture-of-cdk11-genetic-functional-and-medicinal-aspects
#1
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
#2
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
#3
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...
July 19, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28755480/g3bp1-interacts-directly-with-the-fmdv-ires-and-negatively-regulates-translation
#4
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
#5
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
#6
Claire G Vernon, Bryan A Copits, Jacob R Stolz, Yomayra F Guzmán, Geoffrey T Swanson
Ionotropic glutamate receptors (iGluRs) are tetrameric proteins with between 4 and 12 consensus sites for N-glycosylation on each subunit, which potentially allows for a high degree of structural diversity conferred by this post-translational modification. N-glycosylation is required for proper folding of iGluRs in mammalian cells, but the impact of oligosaccharides on the function of successfully folded receptors is less clear. Glycan moieties are large, polar, occasionally charged, and mediate many protein-protein interactions throughout the nervous system...
July 17, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28699639/loss-of-mtorc1-signalling-impairs-%C3%AE-cell-homeostasis-and-insulin-processing
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28666355/mrna-cap-analogues-substituted-in-the-tetraphosphate-chain-with-cx2-identification-of-o-to-ccl2-as-the-first-bridging-modification-that-confers-resistance-to-decapping-without-impairing-translation
#10
Anna M Rydzik, Marcin Warminski, Pawel J Sikorski, Marek R Baranowski, Sylwia Walczak, Joanna Kowalska, Joanna Zuberek, Maciej Lukaszewicz, Elzbieta Nowak, Timothy D W Claridge, Edward Darzynkiewicz, Marcin Nowotny, Jacek Jemielity
Analogues of the mRNA 5΄-cap are useful tools for studying mRNA translation and degradation, with emerging potential applications in novel therapeutic interventions including gene therapy. We report the synthesis of novel mono- and dinucleotide cap analogues containing dihalogenmethylenebisphosphonate moiety (i.e. one of the bridging O atom substituted with CCl2 or CF2) and their properties in the context of cellular translational and decapping machineries, compared to phosphate-unmodified and previously reported CH2-substituted caps...
June 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28666265/cap-dependent-translational-control-of-oncolytic-measles-virus-infection-in-malignant-mesothelioma
#11
Blake A Jacobson, Ahad A Sadiq, Shaogeng Tang, Joe Jay-Dixon, Manish R Patel, Jeremy Drees, Brent S Sorenson, Stephen J Russell, Robert A Kratzke
Malignant mesothelioma has a poor prognosis for which there remains an urgent need for successful treatment approaches. Infection with the Edmonston vaccine strain (MV-Edm) derivative of measles virus results in lysis of cancer cells and has been tested in clinical trials for numerous tumor types including mesothelioma. Many factors play a role in MV-Edm tumor cell selectivity and cytopathic activity while also sparing non-cancerous cells. The MV-Edm receptor CD46 (cluster of differentiation 46) was demonstrated to be significantly higher in mesothelioma cells than in control cells...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28613837/artificial-off-riboswitches-that-downregulate-internal-ribosome-entry-without-hybridization-switches-in-a-eukaryotic-cell-free-translation-system
#12
Atsushi Ogawa, Hiroki Masuoka, Tsubasa Ota
We constructed novel artificial riboswitches that function in a eukaryotic translation system (wheat germ extract), by rationally implanting an in vitro-selected aptamer into the intergenic internal ribosome entry site (IRES) of Plautia stali intestine virus. These eukaryotic OFF-riboswitches (OFF-eRSs) ligand-dose-dependently downregulate IRES-mediated translation without hybridization switches, which typical riboswitches utilize for gene regulation. The hybridization-switch-free mechanism not only allows for easy design but also requires less energy for regulation, resulting in a higher switching efficiency than hybridization-switch-based OFF-eRSs provide...
June 14, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28599981/p90rsk-blockade-inhibits-dual-braf-and-mek-inhibitor-resistant-melanoma-by-targeting-protein-synthesis
#13
Nicholas Theodosakis, Goran Micevic, Casey G Langdon, Alessandra Ventura, Robert Means, David F Stern, Marcus W Bosenberg
Despite improvements in survival in metastatic melanoma with combined BRAF and MEK inhibitor treatment, the overwhelming majority of patients eventually acquire resistance to both agents. Consequently, new targets for therapy in resistant tumors are currently being evaluated. Previous studies have identified p90RSK family kinases as key factors for growth and proliferation, as well as protein synthesis via assembly of the m(7)-GTP cap-dependent translation complex. We sought to evaluate inhibitors of p90RSK family members: BI-D1870 and BRD7389, for their ability to inhibit both proliferation and protein synthesis in patient-derived melanoma cell lines with acquired resistance to combined treatment with the BRAF inhibitor vemurafenib and MEK inhibitor selumetinib...
June 6, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28584194/efficient-and-accurate-translation-initiation-directed-by-tisu-involves-rps3-and-rps10e-binding-and-differential-eukaryotic-initiation-factor-1a-regulation
#14
Ora Haimov, Hadar Sinvani, Franck Martin, Igor Ulitsky, Rafi Emmanuel, Ana Tamarkin-Ben-Harush, Assaf Vardy, Rivka Dikstein
Canonical translation initiation involves ribosomal scanning, but short 5' untranslated region (5'UTR) mRNAs are translated in a scanning-independent manner. The extent and mechanism of scanning-independent translation are not fully understood. Here we report that short 5'UTR mRNAs constitute a substantial fraction of the translatome. Short 5'UTR mRNAs are enriched with TISU (translation initiator of short 5'UTR), a 12-nucleotide element directing efficient scanning-independent translation. Comprehensive mutagenesis revealed that each AUG codon-flanking nucleotide of TISU contributes to translational strength, but only a few are important for accuracy...
August 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28577281/acquired-tamoxifen-resistance-in-mcf-7-breast-cancer-cells-requires-hyperactivation-of-eif4f-mediated-translation
#15
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
#16
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/28559306/a-helicase-independent-activity-of-eif4a-in-promoting-mrna-recruitment-to-the-human-ribosome
#17
Masaaki Sokabe, Christopher S Fraser
In the scanning model of translation initiation, the decoding site and latch of the 40S subunit must open to allow the recruitment and migration of messenger RNA (mRNA); however, the precise molecular details for how initiation factors regulate mRNA accommodation into the decoding site have not yet been elucidated. Eukaryotic initiation factor (eIF) 3j is a subunit of eIF3 that binds to the mRNA entry channel and A-site of the 40S subunit. Previous studies have shown that a reduced affinity of eIF3j for the 43S preinitiation complex (PIC) occurs on eIF4F-dependent mRNA recruitment...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28557706/downregulation-of-p68-rna-helicase-ddx5-activates-a-survival-pathway-involving-mtor-and-mdm2-signals
#18
M Kokolo, M Bach-Elias
The DEAD box p68 RNA helicase (DDX5) is required to manipulate RNA structures implicated in mRNA/rRNA processing and transcript export, and acts as a co-activator for a range of transcription factors. Previous research has indicated that p68 RNA helicase may also be important in tumour development. Wild-type HeLa and stable HeLa (clone 13) cell cultures containing RNAi-mediated depletion of p68 RNA helicase induced by doxycycline (DOX) were used to study how the p68 RNA helicase affects the mTOR cell signalling pathway...
2017: Folia Biologica (Praha)
https://www.readbyqxmd.com/read/28555065/a-novel-micro-cold-atmospheric-plasma-device-for-glioblastoma-both-in-vitro-and-in-vivo
#19
Zhitong Chen, Hayk Simonyan, Xiaoqian Cheng, Eda Gjika, Li Lin, Jerome Canady, Jonathan H Sherman, Colin Young, Michael Keidar
Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. Direct CAP jet irradiation is limited to the skin and it can also be invoked as a supplement therapy during surgery as it only causes cell death in the upper three to five cell layers. However, the current cannulas from which the plasma emanates are too large for intracranial applications. To enhance efficiency and expand the applicability of the CAP method for brain tumors and reduce the gas flow rate and size of the plasma jet, a novel micro-sized CAP device (µCAP) was developed and employed to target glioblastoma tumors in the murine brain...
May 30, 2017: Cancers
https://www.readbyqxmd.com/read/28548627/combined-single-molecule-experimental-and-computational-approaches-for-understanding-the-unfolding-pathway-of-a-viral-translation-enhancer-that-participates-in-a-conformational-switch
#20
My-Tra Le, Wojciech K Kasprzak, Bruce A Shapiro, Anne E Simon
How plus-strand [+]RNA virus genomes transition from translation templates to replication templates is a matter of much speculation. We have previously proposed that, for Turnip crinkle virus, binding of the encoded RNA-dependent RNA polymerase (RdRp) to the 3'UTR of the [+]RNA template promotes a regional wide-spread conformational switch to an alternative structure that disassembles the cap-independent translation element (CITE) in the 3'UTR. The active 3'CITE folds into a tRNA-like T-shaped structure (TSS) that binds to 80S ribosomes and 60S subunits in the P-site...
May 26, 2017: RNA Biology
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