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https://www.readbyqxmd.com/read/28990926/irak2-directs-stimulus-dependent-nuclear-export-of-inflammatory-mrnas
#1
Hao Zhou, Katarzyna Bulek, Xiao Li, Tomasz Herjan, Minjia Yu, Wen Qian, Han Wang, Gao Zhou, Xing Chen, Hui Yang, Lingzi Hong, Junjie Zhao, Luke Qin, Koichi Fukuda, Annette Flotho, Ji Gao, Ashok Dongre, Julie A Carman, Zizhen Kang, Bing Su, Timothy S Kern, Jonathan D Smith, Thomas A Hamilton, Frauke Melchior, Paul L Fox, Xiaoxia Li
Expression of inflammatory genes is determined in part by post-transcriptional regulation of mRNA metabolism but how stimulus- and transcript-dependent nuclear export influence is poorly understood. Here we report a novel pathway in which LPS/TLR4 engagement promotes nuclear localization of IRAK2 to facilitate nuclear export of a specific subset of inflammation related mRNAs for translation in murine macrophages. IRAK2 kinase activity is required for LPS-induced RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation...
October 9, 2017: ELife
https://www.readbyqxmd.com/read/28990563/-ribosomes-synthesis-at-the-heart-of-cell-proliferation
#2
Clément Madru, Nicolas Leulliot, Simon Lebaron
Ribosomes are central to gene expression. Their assembly is a complex and an energy consuming process. Many controls exist to make it possible a fine-tuning of ribosome production adapted to cell needs. In this review, we describe recent advances in the characterisation of the links occurring between ribosome synthesis and cell proliferation control. Defects in ribosome biogenesis directly impede cellular cycle and slow-down proliferation. Among the different factors involved, we could define the 5S particle, a ribosome sub-complex, as a key-regulator of p53 and other tumour suppressors such as pRB...
June 2017: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/28886419/mutation-in-an-exonic-splicing-enhancer-site-causing-chronic-granulomatous-disease
#3
Martin de Boer, Karin van Leeuwen, Judy Geissler, Bernd H Belohradsky, Taco W Kuijpers, Dirk Roos
In a male patient suffering from X-linked chronic granulomatous disease (CGD) we found a c.389G>T mutation in exon 5 of the CYBB gene. We have analyzed why 95% of the transcripts of this gene lacked exon 5, leading to a frameshift and premature termination codon. The mutation was located in a region comprising three putative exonic splicing enhancer binding sites, for SRSF1, SRFS2 and SRFS6, according to the ESEfinder Tool (http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi). With the Analyser Splice Tool we calculated the probability of skipping of exon 5 in CYBB mRNA, and by means of Sroogle the number of putative binding motifs for splicing enhancer and splicing silencer proteins (http://astlab...
July 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28874828/srsf1-suppresses-selection-of-intron-distal-5-splice-site-of-dok7-intron-4-to-generate-functional-full-length-dok-7-protein
#4
Khalid Bin Ahsan, Akio Masuda, Mohammad Alinoor Rahman, Jun-Ichi Takeda, Mohammad Nazim, Bisei Ohkawara, Mikako Ito, Kinji Ohno
Dok-7 is a non-catalytic adaptor protein that facilitates agrin-induced clustering of acetylcholine receptors (AChR) at the neuromuscular junction. Alternative selection of 5' splice sites (SSs) of DOK7 intron 4 generates canonical and frame-shifted transcripts. We found that the canonical full-length Dok-7 enhanced AChR clustering, whereas the truncated Dok-7 did not. We identified a splicing cis-element close to the 3' end of exon 4 by block-scanning mutagenesis. RNA affinity purification and mass spectrometry revealed that SRSF1 binds to the cis-element...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28843252/overexpression-of-antiangiogenic-vascular-endothelial-growth-factor-isoform-and-splicing-regulatory-factors-in-oral-laryngeal-and-pharyngeal-squamous-cell-carcinomas
#5
Patrícia Matos Biselli-Chicote, Joice Matos Biselli, Bianca R Cunha, Rodrigo Castro, José Victor Maniglia, Dalísio de Santi Neto, Eloiza Helena Tajara, José Franscisco de Góis Filho, Erica Erina Fukuyama, Érika Cristina Pavarino, Eny Maria Goloni-Bertollo
Background: Overexpression of proangiogenic vascular endothelial growth factor A family VEGFAxxx is associated with tumor growth and metastasis. The role of the alternatively spliced antiangiogenic family VEGFAxxxb is poorly investigated in head and neck squamous cell carcinomas (HNSCCs). The antiangiogenic isoform binds to bevacizumab and its expression level could influence the treatment response and progression-free survival. In this study, the relative expression of VEGFAxxx and VEGFA165b isoforms and splicing regulatory factors genes was investigated in a series of HNSCCs...
August 27, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28800142/alcohol-mediated-missplicing-of-mcl-1-pre-mrna-is-involved-in-neurotoxicity
#6
Rahsan Sariyer, Francesca I De-Simone, Martina Donadoni, Jan B Hoek, Sulie L Chang, Ilker Kudret Sariyer
BACKGROUND: Heavy and chronic ethanol (EtOH) exposure can cause significant structural and functional damage to the adult brain. The most devastating consequence of EtOH exposure is the neurotoxicity associated with the depletion of neurons. Regulation of splice variants in the brain can modulate protein functions, which may ultimately affect behaviors associated with alcohol dependence and EtOH-mediated neurotoxicity. As alcohol consumption is associated with neurotoxicity, it is possible that altered splicing of survival and pro-survival factors during the development of alcoholism may contribute to the neurotoxicity...
October 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28799539/srsf1-promotes-vascular-smooth-muscle-cell-proliferation-through-a-%C3%AE-133p53-egr1-klf5-pathway
#7
Ning Xie, Min Chen, Rilei Dai, Yan Zhang, Hanqing Zhao, Zhiming Song, Lufeng Zhang, Zhenyan Li, Yuanqing Feng, Hua Gao, Li Wang, Ting Zhang, Rui-Ping Xiao, Jianxin Wu, Chun-Mei Cao
Though vascular smooth muscle cell (VSMC) proliferation underlies all cardiovascular hyperplastic disorders, our understanding of the molecular mechanisms responsible for this cellular process is still incomplete. Here we report that SRSF1 (serine/arginine-rich splicing factor 1), an essential splicing factor, promotes VSMC proliferation and injury-induced neointima formation. Vascular injury in vivo and proliferative stimuli in vitro stimulate SRSF1 expression. Mice lacking SRSF1 specifically in SMCs develop less intimal thickening after wire injury...
August 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28747380/identification-of-differentially-expressed-splice-variants-by-the-proteogenomic-pipeline-splicify
#8
Malgorzata A Komor, Thang V Pham, Annemieke C Hiemstra, Sander R Piersma, Anne S Bolijn, Tim Schelfhorst, Pien M Delis-van Diemen, Marianne Tijssen, Robert P Sebra, Meredith Ashby, Gerrit A Meijer, Connie R Jimenez, Remond J A Fijneman
Proteogenomics, i.e. comprehensive integration of genomics and proteomics data, is a powerful approach identifying novel protein biomarkers. This is especially the case for proteins that differ structurally between disease and control conditions. As tumor development is associated with aberrant splicing, we focus on this rich source of cancer specific biomarkers. To this end, we developed a proteogenomic pipeline, Splicify, which can detect differentially expressed protein isoforms. Splicify is based on integrating RNA massive parallel sequencing data and tandem mass spectrometry proteomics data to identify protein isoforms resulting from differential splicing between two conditions...
October 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28677678/srsf1-dependent-nuclear-export-inhibition-of-c9orf72-repeat-transcripts-prevents-neurodegeneration-and-associated-motor-deficits
#9
Guillaume M Hautbergue, Lydia M Castelli, Laura Ferraiuolo, Alvaro Sanchez-Martinez, Johnathan Cooper-Knock, Adrian Higginbottom, Ya-Hui Lin, Claudia S Bauer, Jennifer E Dodd, Monika A Myszczynska, Sarah M Alam, Pierre Garneret, Jayanth S Chandran, Evangelia Karyka, Matthew J Stopford, Emma F Smith, Janine Kirby, Kathrin Meyer, Brian K Kaspar, Adrian M Isaacs, Sherif F El-Khamisy, Kurt J De Vos, Ke Ning, Mimoun Azzouz, Alexander J Whitworth, Pamela J Shaw
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays...
July 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28652379/the-mutant-p53-id4-complex-controls-vegfa-isoforms-by-recruiting-lncrna-malat1
#10
Magdalena Pruszko, Elisa Milano, Mattia Forcato, Sara Donzelli, Federica Ganci, Silvia Di Agostino, Simone De Panfilis, Francesco Fazi, David O Bates, Silvio Bicciato, Maciej Zylicz, Alicja Zylicz, Giovanni Blandino, Giulia Fontemaggi
The abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with a poorly differentiated and aggressive phenotype of mammary carcinomas. This long non-coding RNA (lncRNA) localizes to nuclear speckles, where it interacts with a subset of splicing factors and modulates their activity. In this study, we demonstrate that oncogenic splicing factor SRSF1 bridges MALAT1 to mutant p53 and ID4 proteins in breast cancer cells. Mutant p53 and ID4 delocalize MALAT1 from nuclear speckles and favor its association with chromatin...
August 2017: EMBO Reports
https://www.readbyqxmd.com/read/28651966/rnacompete-s-combined-rna-sequence-structure-preferences-for-rna-binding-proteins-derived-from-a-single-step-in-vitro-selection
#11
Kate B Cook, Shankar Vembu, Kevin C H Ha, Hong Zheng, Kaitlin U Laverty, Timothy R Hughes, Debashish Ray, Quaid D Morris
RNA-binding proteins recognize RNA sequences and structures, but there is currently no systematic and accurate method to derive large (>12base) motifs de novo that reflect a combination of intrinsic preference to both sequence and structure. To address this absence, we introduce RNAcompete-S, which couples a single-step competitive binding reaction with an excess of random RNA 40-mers to a custom computational pipeline for interrogation of the bound RNA sequences and derivation of SSMs (Sequence and Structure Models)...
June 24, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28576472/redirecting-sr-protein-nuclear-trafficking-through-an-allosteric-platform
#12
Brandon E Aubol, Kendra L Hailey, Laurent Fattet, Patricia A Jennings, Joseph A Adams
Although phosphorylation directs serine-arginine (SR) proteins from nuclear storage speckles to the nucleoplasm for splicing function, dephosphorylation paradoxically induces similar movement, raising the question of how such chemical modifications are balanced in these essential splicing factors. In this new study, we investigated the interaction of protein phosphatase 1 (PP1) with the SR protein splicing factor (SRSF1) to understand the foundation of these opposing effects in the nucleus. We found that RNA recognition motif 1 (RRM1) in SRSF1 binds PP1 and represses its catalytic function through an allosteric mechanism...
July 7, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28513465/the-role-of-srsf1-in-cancer
#13
Elżbieta Sokół, Joanna Bogusławska, Agnieszka Piekiełko-Witkowska
SRSF1 jest wielofunkcyjnym białkiem biorącym udział w procesach związanych z metabolizmem RNA. Następstwem zaburzeń ekspresji SRSF1, obserwowanych w wielu typach nowotworów, są nieprawidłowości w składaniu pre-mRNA, zmiany stabilności transkryptów i poziomu translacji onkogenów oraz genów supresorowych. Regulując różnicowe składanie transkryptów genów CCND1, RAC1, KLF6, BCL2L1, MCL1 oraz CASP9, SRSF1 indukuje zmiany w cyklu komórkowym, proliferacji i apoptozie. Czynnik SRSF1 wpływa także na angiogenezę nowotworową i przerzutowanie, m...
May 17, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28444861/lncrna-malat1-is-dysregulated-in-diabetic-nephropathy-and-involved-in-high-glucose-induced-podocyte-injury-via-its-interplay-with-%C3%AE-catenin
#14
Mengsi Hu, Rong Wang, Xiaobing Li, Minghua Fan, Jiangong Lin, Junhui Zhen, Liqun Chen, Zhimei Lv
Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a long non-coding RNA, broadly expressed in mammalian tissues including kidney and up-regulated in a variety of cancer cells. To date, its functions in podocytes are largely unknown. β-catenin is a key mediator in the canonical and non-canonical Wnt signalling pathway; its aberrant expression promotes podocyte malfunction and albuminuria, and contributes to kidney fibrosis. In this study, we found that MALAT1 levels were increased in kidney cortices from C57BL/6 mice with streptozocin (STZ)-induced diabetic nephropathy, and dynamically regulated in cultured mouse podocytes stimulated with high glucose, which showed a trend from rise to decline...
April 26, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28379520/sumo-conjugation-to-spliceosomal-proteins-is-required-for-efficient-pre-mrna-splicing
#15
Berta Pozzi, Laureano Bragado, Cindy L Will, Pablo Mammi, Guillermo Risso, Henning Urlaub, Reinhard Lührmann, Anabella Srebrow
Pre-mRNA splicing is catalyzed by the spliceosome, a multi-megadalton ribonucleoprotein machine. Previous work from our laboratory revealed the splicing factor SRSF1 as a regulator of the SUMO pathway, leading us to explore a connection between this pathway and the splicing machinery. We show here that addition of a recombinant SUMO-protease decreases the efficiency of pre-mRNA splicing in vitro. By mass spectrometry analysis of anti-SUMO immunoprecipitated proteins obtained from purified splicing complexes formed along the splicing reaction, we identified spliceosome-associated SUMO substrates...
June 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28321468/hyperglycaemic-memory-affects-the-neurovascular-unit-of-the-retina-in-a-diabetic-mouse-model
#16
Patrick Friedrichs, Andrea Schlotterer, Carsten Sticht, Matthias Kolibabka, Paulus Wohlfart, Axel Dietrich, Thomas Linn, Grietje Molema, Hans-Peter Hammes
AIMS/HYPOTHESIS: The aim of this study was to evaluate damage to the neurovascular unit in a mouse model of hyperglycaemic memory. METHODS: A streptozotocin-induced mouse model of diabetes (C57BL/6J background) received insulin-releasing pellets and pancreatic islet-cell transplantation. Damage to the neurovascular unit was studied by quantitative retinal morphometry for microvascular changes and microarray analysis, with subsequent functional annotation clustering, for changes of the retinal genome...
July 2017: Diabetologia
https://www.readbyqxmd.com/read/28315432/splicing-factors-of-sr-and-hnrnp-families-as-regulators-of-apoptosis-in-cancer
#17
REVIEW
Hanna Kędzierska, Agnieszka Piekiełko-Witkowska
SR and hnRNP proteins were initially discovered as regulators of alternative splicing: the process of controlled removal of introns and selective joining of exons through which multiple transcripts and, subsequently, proteins can be expressed from a single gene. Alternative splicing affects genes involved in all crucial cellular processes, including apoptosis. During cancerogenesis impaired apoptotic control facilitates survival of cells bearing molecular aberrations, contributing to their unrestricted proliferation and chemoresistance...
June 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28286323/switchsense-a-new-technology-to-study-protein-rna-interactions
#18
Antoine Cléry, Thibault J M Sohier, Thomas Welte, Andreas Langer, Frédéric H T Allain
Characterization of RNA-binding protein interactions with RNA became inevitable to properly understand the cellular mechanisms involved in gene expression regulation. Structural investigations bring information at the atomic level on these interactions and complementary methods such as Isothermal Titration Calorimetry (ITC) and Surface Plasmon Resonance (SPR) are commonly used to quantify the affinity of these RNA-protein complexes and evaluate the effect of mutations affecting these interactions. The switchSENSE technology has recently been developed and already successfully used to investigate protein interactions with different types of binding partners (DNA, protein/peptide or even small molecules)...
March 9, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28235482/srsf1-3-contributes-to-diversification-of-the-immunoglobulin-variable-region-gene-by-promoting-accumulation-of-aid-in-the-nucleus
#19
Yuka Kawaguchi, Hiroaki Nariki, Naoko Kawamoto, Yuichi Kanehiro, Satoshi Miyazaki, Mari Suzuki, Masaki Magari, Hiroshi Tokumitsu, Naoki Kanayama
Activation-induced cytidine deaminase (AID) is essential for diversification of the Ig variable region (IgV). AID is excluded from the nucleus, where it normally functions. However, the molecular mechanisms responsible for regulating AID localization remain to be elucidated. The SR-protein splicing factor SRSF1 is a nucleocytoplasmic shuttling protein, a splicing isoform of which called SRSF1-3, has previously been shown to contribute to IgV diversification in chicken DT40 cells. In this study, we examined whether SRSF1-3 functions in IgV diversification by promoting nuclear localization of AID...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28135068/development-of-potent-selective-srpk1-inhibitors-as-potential-topical-therapeutics-for-neovascular-eye-disease
#20
Jennifer Batson, Hamish D Toop, Clara Redondo, Roya Babaei-Jadidi, Apirat Chaikuad, Stephen F Wearmouth, Brian Gibbons, Claire Allen, Cynthia Tallant, Jingxue Zhang, Chunyun Du, Jules C Hancox, Tom Hawtrey, Joana Da Rocha, Renate Griffith, Stefan Knapp, David O Bates, Jonathan C Morris
Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity...
March 17, 2017: ACS Chemical Biology
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