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J Santo, C Lopez-Herrera, C Apolit, Y Bareche, L Lapasset, C Chavey, S Capozi, F Mahuteau, R Najman, P Fornarelli, I C Lopez-Mejía, G Béranger, F Casas, E-Z Amri, B Pau, D Scherrer, J Tazi
BAKGROUND/OBJECTIVES: Intense drug discovery efforts in the metabolic field highlight the need for novel strategies for the treatment of obesity. Alternative splicing (AS) and/or polyadenylation enable the LMNA gene to express distinct protein isoforms that exert opposing effects on energy metabolism and lifespan. Here we aimed to use the splicing factor SRSF1 that contribute to the production of these different isoforms as a target to uncover new anti-obesity drug. SUBJECTS/METHODS: Small molecules modulating SR protein activity and splicing, were tested for their abilities to interact with SRSF1 and to modulate LMNA (AS)...
December 5, 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Richard P Hulse, Robert A R Drake, David O Bates, Lucy F Donaldson
Neuropathic pain results from neuroplasticity in nociceptive neuronal networks. Here we demonstrate that control of alternative pre-mRNA splicing, through the splice factor serine-arginine splice factor 1 (SRSF1), is integral to the processing of nociceptive information in the spinal cord. Neuropathic pain develops following a partial saphenous nerve ligation injury, at which time SRSF1 is activated in damaged myelinated primary afferent neurons, with minimal found in small diameter (IB4 positive) dorsal root ganglia neurons...
December 2016: Neurobiology of Disease
Tiing Jen Loh, Heegyum Moon, Ha Na Jang, Yongchao Liu, Namjeong Choi, Shengfu Shen, Darren Reece Williams, Da-Woon Jung, Xuexiu Zheng, Haihong Shen
CD44 pre-mRNA includes 20 exons, among which exons1-5 (C1-C5) and exons16-20 (C6-C10) are constant exons, whereas exons 6-15 (V1-V10) are variant exons. V6 exon containing isoforms has been known to be implicated in tumor cell invasion and metastasis. In the present study, we performed SR protein screen for CD44 V6 splicing using overexpression and lentivirus-mediated shRNA treatment. Using CD44 V6 minigene, we demonstrate that increased SRSF3 and SRSF4 expression do not affect V6 splicing, but increased expression of SRSF1, SRSF6 and SRSF9 inhibit V6 splicing significantly...
August 17, 2016: BMB Reports
Anshika Goenka, Sonali Sengupta, Rajesh Pandey, Rashmi Parihar, Girish Chandra Mohanta, Mitali Mukerji, Subramaniam Ganesh
The heat shock response is a conserved defense mechanism that protects cells from physiological stress, including thermal stress. Besides the activation of heat-shock-protein genes, the heat shock response is also known to bring about global suppression of transcription; however, the mechanism by which this occurs is poorly understood. One of the intriguing aspects of the heat shock response in human cells is the transcription of satellite-III (Sat3) long non-coding RNAs and their association with nuclear stress bodies (nSBs) of unknown function...
October 1, 2016: Journal of Cell Science
Pushkar Malakar, Lital Chartarifsky, Ayat Hija, Gil Leibowitz, Benjamin Glaser, Yuval Dor, Rotem Karni
Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells...
2016: Scientific Reports
Li Yang, Yang Tang, Fang'Xi Xiao, Jie Xiong, Ke'Feng Shen, Ya'Nan Liu, Wei Zhang, Li'Chang Zheng, Jian'Feng Zhou, Min Xiao
STUDY PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages. In this study, we aimed to explore the genetic factors involved in the pathogenesis of both acquired and familial type HLH. METHOD: The ION TORRENT semi-conductor sequencing method was used to sequence samples from 10 patients who were diagnosed or highly suspected of HLH...
2016: PloS One
Soo-Ho Lee, Hyun-Kyung Lee, Chowon Kim, Yoo-Kyung Kim, Tayaba Ismail, Youngeun Jeong, Kyeongyeon Park, Jeen-Woo Park, Oh-Shin Kwon, Beom Sik Kang, Dong-Seok Lee, Mae-Ja Park, Do-Sim Park, Hyun-Shik Lee
Alternative splicing is a major mechanism regulating pattern of gene expression through the production of multiple mRNAs from a single gene transcript. Any misregulation can cause various human diseases and also have severe effects on embryogenesis. SRSF1 is one of the critical factors regulating alternative splicing at many stages of vertebrate development and any disturbance in SRSF1 leads to serious consequences. In current study, we investigated the effects of loss of the SRSF1 gene using antisense morpholino oligonucleotides (MO) in Xenopus embryogenesis...
September 2, 2016: Biochemical and Biophysical Research Communications
Won Cheol Park, Hak-Ryul Kim, Dong Baek Kang, Jae-Suk Ryu, Keum-Ha Choi, Gyeong-Ok Lee, Ki Jung Yun, Keun Young Kim, Raekil Park, Kwon-Ha Yoon, Ji-Hyun Cho, Young-Jin Lee, Soo-Cheon Chae, Min-Cheol Park, Do-Sim Park
BACKGROUND: Serine/arginine-rich splicing factors (SRSFs) and HNRNPA1 have oncogenic properties. However, their proteomic expressions and practical priority in gastric cancer (GC) and colorectal cancer (CRC) are mostly unknown. To apply SFs in clinics, effective marker selection and characterization of properties in the target organ are essential. METHODS: We concurrently analyzed SRSF1, 3, and 5-7, and HNRNPA1, together with the conventional tumor marker carcinoembryonic antigen (CEA), in stomach and colorectal tissue samples (n = 420) using semiquantitative immunoblot, subcellular fractionation, and quantitative real-time polymerase chain reaction methods...
2016: BMC Cancer
Ilker Kudret Sariyer, Rahsan Sariyer, Jessica Otte, Jennifer Gordon
OBJECTIVE: PML is a rare and fatal demyelinating disease of the CNS caused by the human polyomavirus, JC virus (JCV), which occurs in AIDS patients and those on immunosuppressive monoclonal antibody therapies (mAbs). We sought to identify mechanisms that could stimulate reactivation of JCV in a cell culture model system and targeted pathways which could affect early gene transcription and JCV T-antigen production, which are key steps of the viral life cycle for blocking reactivation of JCV...
2016: PloS One
Sze Jing Tang, Shufang Luo, Jia Xin Jessie Ho, Phuong Thao Ly, Eling Goh, Xavier Roca
Here we present a detailed analysis of the alternative splicing regulation of human CD46, which generates different isoforms with distinct functions. CD46 is a ubiquitous membrane protein that protects host cells from complement and plays other roles in immunity, autophagy, and cell adhesion. CD46 deficiency causes an autoimmune disorder, and this protein is also involved in pathogen infection and cancer. Before this study, the mechanisms of CD46 alternative splicing remained unexplored even though dysregulation of this process has been associated with autoimmune diseases...
July 1, 2016: Journal of Biological Chemistry
Miroslav Krepl, Antoine Cléry, Markus Blatter, Frederic H T Allain, Jiri Sponer
RNA recognition motif (RRM) proteins represent an abundant class of proteins playing key roles in RNA biology. We present a joint atomistic molecular dynamics (MD) and experimental study of two RRM-containing proteins bound with their single-stranded target RNAs, namely the Fox-1 and SRSF1 complexes. The simulations are used in conjunction with NMR spectroscopy to interpret and expand the available structural data. We accumulate more than 50 μs of simulations and show that the MD method is robust enough to reliably describe the structural dynamics of the RRM-RNA complexes...
July 27, 2016: Nucleic Acids Research
Liyan Jiang, Jiaqi Huang, Brandon W Higgs, Zhibin Hu, Zhan Xiao, Xin Yao, Sarah Conley, Haihong Zhong, Zheng Liu, Philip Brohawn, Dong Shen, Song Wu, Xiaoxiao Ge, Yue Jiang, Yizhuo Zhao, Yuqing Lou, Chris Morehouse, Wei Zhu, Yinong Sebastian, Meggan Czapiga, Vaheh Oganesyan, Haihua Fu, Yanjie Niu, Wei Zhang, Katie Streicher, David Tice, Heng Zhao, Meng Zhu, Lin Xu, Ronald Herbst, Xinying Su, Yi Gu, Shyoung Li, Lihua Huang, Jianren Gu, Baohui Han, Bahija Jallal, Hongbing Shen, Yihong Yao
Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss...
April 2016: PLoS Genetics
Pedro Serrano, Brandon E Aubol, Malik M Keshwani, Stefano Forli, Chen-Ting Ma, Samit K Dutta, Michael Geralt, Kurt Wüthrich, Joseph A Adams
Multisite phosphorylation is required for the biological function of serine-arginine (SR) proteins, a family of essential regulators of mRNA splicing. These modifications are catalyzed by serine-arginine protein kinases (SRPKs) that phosphorylate numerous serines in arginine-serine-rich (RS) domains of SR proteins using a directional, C-to-N-terminal mechanism. The present studies explore how SRPKs govern this highly biased phosphorylation reaction and investigate biological roles of the observed directional phosphorylation mechanism...
June 5, 2016: Journal of Molecular Biology
Yuanming Cheng, Chunling Luo, Wenwu Wu, Zhiqin Xie, Xiangdong Fu, Ying Feng
The liver performs a variety of unique functions critical for metabolic homeostasis. Here, we show that mice lacking the splicing factor SRSF2 but not SRSF1 in hepatocytes have severe liver pathology and biochemical abnormalities. Histological analyses revealed generalized hepatitis with the presence of ballooned hepatocytes and evidence of fibrosis. Molecular analysis demonstrated that SRSF2 governs splicing of multiple genes involved in the stress-induced cell death pathway in the liver. More importantly, SRSF2 also functions as a potent transcription activator, required for efficient expression of transcription factors mainly responsible for energy homeostasis and bile acid metabolism in the liver...
June 1, 2016: Molecular and Cellular Biology
Stasė Butkytė, Laurynas Čiupas, Eglė Jakubauskienė, Laurynas Vilys, Paulius Mocevicius, Arvydas Kanopka, Giedrius Vilkaitis
BACKGROUND: An abundant class of intronic microRNAs (miRNAs) undergoes atypical Drosha-independent biogenesis in which the spliceosome governs the excision of hairpin miRNA precursors, called mirtrons. Although nearly 500 splicing-dependent miRNA candidates have been recently predicted via bioinformatic analysis of human RNA-Seq datasets, only a few of them have been experimentally validated. The detailed mechanism of miRNA processing by the splicing machinery and the roles of mirtronic miRNAs in cancer are yet to be uncovered...
2016: Clinical Epigenetics
Lindsey Skrdlant, Ren-Jang Lin
SR proteins are a class of RNA-binding proteins whose RNA-binding ability is required for both constitutive and alternative splicing. While members of the SR protein family were once thought to have redundant functions, in-depth biochemical analysis of their RNA-binding abilities has revealed distinct binding profiles for each SR protein, that often lead to either synergistic or antagonistic functions. SR protein family members SRSF1 and SRSF2 are two of the most highly studied RNA-binding proteins. Here we examine the various methods used to differentiate SRSF1 and SRSF2 RNA-binding ability...
2016: Methods in Molecular Biology
T Klymenko, H Hernandez-Lopez, A I MacDonald, J M Bodily, S V Graham
UNLABELLED: The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelial cell, suggesting a sophisticated interplay between host cell metabolism and virus replication. Previously, we demonstrated in differentiated keratinocytes in vitro and in vivo that HPV type 16 (HPV16) infection caused increased levels of the cellular SR splicing factors (SRSFs) SRSF1 (ASF/SF2), SRSF2 (SC35), and SRSF3 (SRp20). Moreover, the viral E2 transcription and replication factor that is expressed at high levels in differentiating keratinocytes could bind and control activity of the SRSF1 gene promoter...
May 15, 2016: Journal of Virology
Rahsan Sariyer, Francesca Isabella De-Simone, Jennifer Gordon, Ilker Kudret Sariyer
Progressive multifocal leukoemcephalopathy (PML) is a fatal demyelinating disease caused by the human neurotropic JC virus (JCV). JCV infects the majority of the human population during childhood and establishes a latent/persistent life-long infection. The virus reactivates under immunosuppressive conditions by unknown mechanisms, resulting in productive infection of oligodendrocytes in the central nervous system (CNS). Given the fact that the natural occurrence of PML is strongly associated with immunosuppression, the functional and molecular interaction between glial cells and neuroimmune signaling mediated by soluble immune mediators is likely to play a major role in reactivation of JCV and the progression of the lytic viral life cycle leading to the development of PML...
October 2016: Journal of Neurovirology
Michaela Müller-McNicoll, Valentina Botti, Antonio M de Jesus Domingues, Holger Brandl, Oliver D Schwich, Michaela C Steiner, Tomaz Curk, Ina Poser, Kathi Zarnack, Karla M Neugebauer
Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP)...
March 1, 2016: Genes & Development
Anne Cammas, Magali Lacroix-Triki, Sandra Pierredon, Morgane Le Bras, Jason S Iacovoni, Marie-Paule Teulade-Fichou, Gilles Favre, Henri Roché, Thomas Filleron, Stefania Millevoi, Stéphan Vagner
The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis...
March 29, 2016: Oncotarget
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