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https://www.readbyqxmd.com/read/28677678/srsf1-dependent-nuclear-export-inhibition-of-c9orf72-repeat-transcripts-prevents-neurodegeneration-and-associated-motor-deficits
#1
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
#2
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...
June 26, 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
#3
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 (>12 base) 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 23, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28576472/redirecting-sr-protein-nuclear-trafficking-through-an-allosteric-platform
#4
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...
May 31, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28513465/the-role-of-srsf1-in-cancer
#5
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
#6
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
#7
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...
March 30, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28321468/hyperglycaemic-memory-affects-the-neurovascular-unit-of-the-retina-in-a-diabetic-mouse-model
#8
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...
March 20, 2017: Diabetologia
https://www.readbyqxmd.com/read/28315432/splicing-factors-of-sr-and-hnrnp-families-as-regulators-of-apoptosis-in-cancer
#9
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...
March 14, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28286323/switchsense-a-new-technology-to-study-protein-rna-interactions
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28119102/suppression-of-5-splice-sites-through-multiple-exonic-motifs-by-hnrnp-l
#13
Tiing Jen Loh, Namjeong Choi, Heegyum Moon, Ha Na Jang, Yongchao Liu, Jianhua Zhou, Xuexiu Zheng, Haihong Shen
Selection of 5' splice-sites (5'SS) in alternative splicing plays an important role in gene regulation. Although regulatory mechanisms of heterogeneous nuclear ribonucleoprotein L (hnRNP L), a well-known splicing regulatory protein, have been studied in a substantial level, its role in 5'SS selection is not thoroughly defined. By using a KLF6 pre-mRNA alternative splicing model, we demonstrate in this report that hnRNP L inhibits proximal 5'SS but promotes two consecutive distal 5'SS splicing, antagonizing SRSF1 roles in KLF6 pre-mRNA splicing...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28072465/splicing-regulation-and-dysregulation-of-cholinergic-genes-expressed-at-the-neuromuscular-junction
#14
REVIEW
Kinji Ohno, Mohammad Alinoor Rahman, Mohammad Nazim, Farhana Nasrin, Yingni Lin, Jun-Ichi Takeda, Akio Masuda
We humans have evolved by acquiring diversity of alternative RNA metabolisms including alternative means of splicing and transcribing non-coding genes, and not by acquiring new coding genes. Tissue-specific and developmental stage-specific alternative RNA splicing is achieved by tightly regulated spatiotemporal regulation of expressions and activations of RNA-binding proteins that recognize their cognate splicing cis-elements on nascent RNA transcripts. Genes expressed at the neuromuscular junction (NMJ) are also alternatively spliced...
January 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28069438/ribosomal-protein-pno40-mediates-nucleolar-sequestration-of-sr-family-splicing-factors-and-its-overexpression-impairs-mrna-metabolism
#15
Yen-Ming Lin, Pao-Hsien Chu, Yun-Zhu Li, Pin Ouyang
The nucleolus acts as a key stress sensor and responds to changes in cellular growth rate and metabolic activity. In addition to its major role as the site of ribosome biogenesis, high-throughput proteomic analyses of purified nucleoli have highlighted the multi-functional nature of these organelles, and several SR family splicing factors, including SRSF1 and SRSF2, have been detected in human nucleolar proteome analysis. Here we provide evidence that pNO40, a 60s ribosomal protein associated with nucleoli, acts as a mediator for recruitment of SR family splicing factors into nucleoli...
January 6, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28064149/emerging-roles-for-rna-binding-proteins-as-effectors-and-regulators-of-cardiovascular-disease
#16
Ruben G de Bruin, Ton J Rabelink, Anton Jan van Zonneveld, Eric P van der Veer
The cardiovascular system comprises multiple cell types that possess the capacity to modulate their phenotype in response to acute or chronic injury. Transcriptional and post-transcriptional mechanisms play a key role in the regulation of remodelling and regenerative responses to damaged cardiovascular tissues. Simultaneously, insufficient regulation of cellular phenotype is tightly coupled with the persistence and exacerbation of cardiovascular disease. Recently, RNA-binding proteins such as Quaking, HuR, Muscleblind, and SRSF1 have emerged as pivotal regulators of these functional adaptations in the cardiovascular system by guiding a wide-ranging number of post-transcriptional events that dramatically impact RNA fate, including alternative splicing, stability, localization and translation...
May 7, 2017: European Heart Journal
https://www.readbyqxmd.com/read/27999187/targeting-the-pro-angiogenic-forms-of-vegf-or-inhibiting-their-expression-as-anti-cancer-strategies
#17
Mélanie Guyot, Caroline Hilmi, Damien Ambrosetti, Marco Merlano, Cristiana Lo Nigro, Jérôme Durivault, Renaud Grépin, Gilles Pagès
Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ)...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27993818/long-noncoding-rna-malat1-promotes-hepatocellular-carcinoma-development-by-srsf1-upregulation-and-mtor-activation
#18
Pushkar Malakar, Asaf Shilo, Adi Mogilevsky, Ilan Stein, Eli Pikarsky, Yuval Nevo, Hadar Benyamini, Sharona Elgavish, Xinying Zong, Kannanganattu V Prasanth, Rotem Karni
Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of antiapoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/27984373/hnrnpa1-a-splicing-regulator-is-an-effective-target-protein-for-cervical-cancer-detection-comparison-with-conventional-tumor-markers
#19
Young-Jon Kim, Byoung-Ryun Kim, Jae-Suk Ryu, Gyeong-Ok Lee, Hak-Ryul Kim, Keum-Ha Choi, Jae-Won Ryu, Kyoung-Suk Na, Min-Cheol Park, Hong-Seob So, Ji-Hyun Cho, Do-Sim Park
OBJECTIVE: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), serine/arginine-rich splicing factor 1 (SRSF1), and SRSF3 are splicing regulators associated with oncogenesis. However, the alterations of SF proteins and their diagnostic values in cervical cancer are unclear. To apply SFs clinically, effective marker selection and characterization of the target organ properties are essential. MATERIALS AND METHODS: We concurrently analyzed HNRNPA1, SRSF1, SRSF3, and the conventional tumor markers squamous cell carcinoma antigen (SCCA) and carcinoembryonic antigen (CEA) in cervical tissue samples (n = 127) using semiquantitative immunoblotting...
February 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/27935425/how-is-herstatin-a-tumor-suppressor-splice-variant-of-the-oncogene-her2-regulated
#20
Marco Silipo, Hannah Gautrey, Swapna Satam, Thomas Lennard, Alison Tyson-Capper
The human epidermal growth factor receptor 2 (HER2)/receptor tyrosine-protein kinasebB-2 (ERBB2) is overexpressed in 20-30% of breast tumors leading to faster growing and more aggressive tumors. Alternative splicing generates a functionally distinct HER2 variant called Herstatin, which is produced by the inclusion of intron 8. Herstatin acts as a tumor suppressor by effectively blocking HER2 activity and cell proliferation, while promoting apoptosis. In the present study we investigated HER2 pre-mRNA regulatory sequences and splicing factors which regulate the alternative splicing of Herstatin...
May 4, 2017: RNA Biology
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