Structural and Functional Studies of Mrna Stability Regulators
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Large-Scale Analysis of Genome and Transcriptome Alterations in Multiple Tumors Unveils Novel Cancer-Relevant Splicing Networks
Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks Endre Sebestyén,1,5 Babita Singh,1,5 Belén Miñana,1,2 Amadís Pagès,1 Francesca Mateo,3 Miguel Angel Pujana,3 Juan Valcárcel,1,2,4 and Eduardo Eyras1,4 1Universitat Pompeu Fabra, E08003 Barcelona, Spain; 2Centre for Genomic Regulation, E08003 Barcelona, Spain; 3Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L’Hospitalet del Llobregat, Spain; 4Catalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We system- atically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alter- natively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferen- tiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome am- plification in nontumorigenic mammary epithelial cells. -
TINCR Inhibits the Proliferation and Invasion of Laryngeal Squamous Cell
He et al. BMC Cancer (2021) 21:753 https://doi.org/10.1186/s12885-021-08513-0 RESEARCH ARTICLE Open Access TINCR inhibits the proliferation and invasion of laryngeal squamous cell carcinoma by regulating miR-210/BTG2 Guoqing He1†, Rui Pang2†, Jihua Han2, Jinliang Jia2, Zhaoming Ding2, Wen Bi2, Jiawei Yu2, Lili Chen2, Jiewu Zhang2* and Yanan Sun1* Abstract Background: Terminal differentiation-induced ncRNA (TINCR) plays an essential role in epidermal differentiation and is involved in the development of various cancers. Methods: qPCR was used to detect the expression level of TINCR in tissues and cell lines of laryngeal squamous cell carcinoma (LSCC). The potential targets of TINCR were predicted by the bioinformation website. The expression of miR-210 and BTG2 genes were detected by qPCR, and the protein levels of BTG2 and Ki-67 were evaluated by western blot. CCK-8 assay, scratch test, and transwell chamber were used to evaluate the proliferation, invasion, and metastasis ability of LSCC cells. The relationships among TINCR, miR-210, and BTG2 were investigated by bioinformatics software and luciferase reporter assay. The in vivo function of TINCR was accessed on survival rate and tumor growth in nude mice. Results: We used qRT-PCR to detect the expression of TINCR in laryngeal squamous cell carcinoma (LSCC) tissues and cells and found significantly lower levels in cancer tissues compared with adjacent tissues. Additionally, patients with high TINCR expression had a better prognosis. TINCR overexpression was observed to inhibit the proliferation and invasion of LSCC cells. TINCR was shown to exert its antiproliferation and invasion effects by adsorbing miR- 210, which significantly promoted the proliferation and invasion of laryngeal squamous cells. -
BTG2: a Rising Star of Tumor Suppressors (Review)
INTERNATIONAL JOURNAL OF ONCOLOGY 46: 459-464, 2015 BTG2: A rising star of tumor suppressors (Review) BIjING MAO1, ZHIMIN ZHANG1,2 and GE WANG1 1Cancer Center, Institute of Surgical Research, Daping Hospital, Third Military Medical University, Chongqing 400042; 2Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, Hubei 430070, P.R. China Received September 22, 2014; Accepted November 3, 2014 DOI: 10.3892/ijo.2014.2765 Abstract. B-cell translocation gene 2 (BTG2), the first 1. Discovery of BTG2 in TOB/BTG gene family gene identified in the BTG/TOB gene family, is involved in many biological activities in cancer cells acting as a tumor The TOB/BTG genes belong to the anti-proliferative gene suppressor. The BTG2 expression is downregulated in many family that includes six different genes in vertebrates: TOB1, human cancers. It is an instantaneous early response gene and TOB2, BTG1 BTG2/TIS21/PC3, BTG3 and BTG4 (Fig. 1). plays important roles in cell differentiation, proliferation, DNA The conserved domain of BTG N-terminal contains two damage repair, and apoptosis in cancer cells. Moreover, BTG2 regions, named box A and box B, which show a high level of is regulated by many factors involving different signal path- homology to the other domains (1-5). Box A has a major effect ways. However, the regulatory mechanism of BTG2 is largely on cell proliferation, while box B plays a role in combination unknown. Recently, the relationship between microRNAs and with many target molecules. Compared with other family BTG2 has attracted much attention. MicroRNA-21 (miR-21) members, BTG1 and BTG2 have an additional region named has been found to regulate BTG2 gene during carcinogenesis. -
Downloaded from the TCGA Data Portal ( Data.Nci.Nih.Gov/Tcga/) (Supplemental Table S1)
bioRxiv preprint doi: https://doi.org/10.1101/023010; this version posted February 11, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks Endre Sebestyén1,*, Babita Singh1,*, Belén Miñana1,2, Amadís Pagès1, Francesca Mateo3, Miguel Angel Pujana3, Juan Valcárcel1,2,4, Eduardo Eyras1,4,5 1Universitat Pompeu Fabra, Dr. Aiguader 88, E08003 Barcelona, Spain 2Centre for Genomic Regulation, Dr. Aiguader 88, E08003 Barcelona, Spain 3Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L’Hospitalet del Llobregat, Spain. 4Catalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23, E08010 Barcelona, Spain *Equal contribution 5Correspondence to: [email protected] Keywords: alternative splicing, RNA binding proteins, splicing networks, cancer 1 bioRxiv preprint doi: https://doi.org/10.1101/023010; this version posted February 11, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. -
Integrative Differential Expression and Gene Set Enrichment Analysis Using Summary Statistics for Scrna-Seq Studies
ARTICLE https://doi.org/10.1038/s41467-020-15298-6 OPEN Integrative differential expression and gene set enrichment analysis using summary statistics for scRNA-seq studies ✉ Ying Ma 1,7, Shiquan Sun 1,7, Xuequn Shang2, Evan T. Keller 3, Mengjie Chen 4,5 & Xiang Zhou 1,6 Differential expression (DE) analysis and gene set enrichment (GSE) analysis are commonly applied in single cell RNA sequencing (scRNA-seq) studies. Here, we develop an integrative 1234567890():,; and scalable computational method, iDEA, to perform joint DE and GSE analysis through a hierarchical Bayesian framework. By integrating DE and GSE analyses, iDEA can improve the power and consistency of DE analysis and the accuracy of GSE analysis. Importantly, iDEA uses only DE summary statistics as input, enabling effective data modeling through com- plementing and pairing with various existing DE methods. We illustrate the benefits of iDEA with extensive simulations. We also apply iDEA to analyze three scRNA-seq data sets, where iDEA achieves up to five-fold power gain over existing GSE methods and up to 64% power gain over existing DE methods. The power gain brought by iDEA allows us to identify many pathways that would not be identified by existing approaches in these data. 1 Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA. 2 School of Computer Science, Northwestern Polytechnical University, Xi’an, Shaanxi 710072, P.R. China. 3 Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. 4 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. 5 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. -
Original Article Long Noncoding RNA TOB1-AS1, an Epigenetically Silenced Gene, Functioned As a Novel Tumor Suppressor by Sponging Mir-27B in Cervical Cancer
Am J Cancer Res 2018;8(8):1483-1498 www.ajcr.us /ISSN:2156-6976/ajcr0079106 Original Article Long noncoding RNA TOB1-AS1, an epigenetically silenced gene, functioned as a novel tumor suppressor by sponging miR-27b in cervical cancer Jihang Yao1, Zhenghong Li1, Ziwei Yang2, Hui Xue1, Hua Chang1, Xue Zhang1, Tianren Li1, Kejun Guo1 Departments of 1Gynecology, 2Clinical Laboratory, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China Received April 21, 2018; Accepted July 9, 2018; Epub August 1, 2018; Published August 15, 2018 Abstract: Cervical cancer is one of the most common cancers in females, accounting for a majority of cancer- related deaths in worldwide. Long non-coding RNAs (lncRNAs) have been identified as critical regulators in many tumor-related biological processes. Thus, investigation into the function and mechanism of lncRNAs in the develop- ment of cervical cancer is very necessary. In this study, we found that the expression of TOB1-AS1 was significantly decreased in cervical cancer tissues compared with the adjacent normal tissues. The methylation status of TOB1- AS1-related CpG island was analyzed using methylation specific PCR and bisulfite sequencing analysis, revealing that the aberrant hypermethylation of TOB1-AS1-related CpG island was frequently observed in primary tumors and cervical cancer cells. The expression of TOB1-AS1 in cervical cancer cells could be reversed by demethylation agent treatment. Functionally, overexpression of TOB1-AS1 significantly inhibited cell proliferation, cell cycle progression, invasion and induced apoptosis, while knockdown of TOB1-AS1 exhibited the opposite effect. Furthermore, it was determined that TOB1-AS1 was able to bind and degrade the expression of miR-27b. -
1 Title 1 Loss of PABPC1 Is Compensated by Elevated PABPC4
bioRxiv preprint doi: https://doi.org/10.1101/2021.02.07.430165; this version posted February 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 1 Title 2 Loss of PABPC1 is compensated by elevated PABPC4 and correlates with transcriptome 3 changes 4 5 Jingwei Xie1, 2, Xiaoyu Wei1, Yu Chen1 6 7 1 Department of Biochemistry and Groupe de recherche axé sur la structure des 8 protéines, McGill University, Montreal, Quebec H3G 0B1, Canada 9 10 2 To whom correspondence should be addressed: Dept. of Biochemistry, McGill 11 University, Montreal, QC H3G 0B1, Canada. E-mail: [email protected]. 12 13 14 15 Abstract 16 Cytoplasmic poly(A) binding protein (PABP) is an essential translation factor that binds to 17 the 3' tail of mRNAs to promote translation and regulate mRNA stability. PABPC1 is the 18 most abundant of several PABP isoforms that exist in mammals. Here, we used the 19 CRISPR/Cas genome editing system to shift the isoform composition in HEK293 cells. 20 Disruption of PABPC1 elevated PABPC4 levels. Transcriptome analysis revealed that the 21 shift in the dominant PABP isoform was correlated with changes in key transcriptional 22 regulators. This study provides insight into understanding the role of PABP isoforms in 23 development and differentiation. 24 Keywords 25 PABPC1, PABPC4, c-Myc 26 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.07.430165; this version posted February 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins
Biomolecules 2015, 5, 1441-1466; doi:10.3390/biom5031441 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Article Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins Rebecca Bish 1,†, Nerea Cuevas-Polo 1,†, Zhe Cheng 1, Dolores Hambardzumyan 2, Mathias Munschauer 3, Markus Landthaler 3 and Christine Vogel 1,* 1 Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, USA; E-Mails: [email protected] (R.B.); [email protected] (N.C.-P.); [email protected] (Z.C.) 2 The Cleveland Clinic, Department of Neurosciences, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA; E-Mail: [email protected] 3 RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Robert-Rössle-Str. 10, Berlin 13092, Germany; E-Mails: [email protected] (M.M.); [email protected] (M.L.) † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-212-998-3976; Fax: +1-212-995-4015. Academic Editor: André P. Gerber Received: 10 May 2015 / Accepted: 15 June 2015 / Published: 15 July 2015 Abstract: DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. -
Inactivation of Erk1 and Erk2 Disrupts Cortical
INACTIVATION OF ERK1 AND ERK2 DISRUPTS CORTICAL PROGENITOR PROLIFERATION LEADING TO ABNORMAL CYTOARCHITECTURE, CIRCUITRY AND BEHAVIOR, MODELING HUMAN NCFC AND RELATED SYNDROMES. by JOANNA PUCILOWSKA Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Gary E. Landreth Department of Neurosciences CASE WESTERN RESERVE UNIVERSITY August 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Joanna Pucilowska candidate for the PhD degree*. (signed) Robert Miller (chair of the committee) Gary Landreth Jerry Silver Stephen Maricich (date) 5/29/2012 *We also certify that written approval has been obtained for any proprietary material contained within. 2 TABLE OF CONTENTS List of figures……...……………………………………………………………….….6 ABSTRACT…...………………………………………………………………….…..9 CHAPTER 1: INTRODUCTION………………………………………………………….11 MAP KINASE Signaling Pathway………………………………………………...11 MAPK Specificity: The Right Place at the Right Time………………………..…16 ERKs and Isoform Specificity………………..…………………………………….23 ERKs in Learning and Memory………………………..………………………….26 ERKs and their FGF Ligands………………………..…………………………….28 CORTICAL DEVELOPMENT: Forebrain Regionalization and Morphogenesis………..…………………31 The Role of Cell Cycle in Corticogenesis……..…………...………………33 ERKs and the Cell Cycle Progression…………………..…………………36 Progenitor Proliferation and Neurogenesis………………..……………...39 Migration…………………..………………………………………………..45 Gliogenesis…………………………………………………………..………47 Differentiation……………………………………………………..………..48 -
BTG2 Loss and Mir-21 Upregulation Contribute to Prostate Cell Transformation by Inducing Luminal Markers Expression and Epithelial–Mesenchymal Transition
Oncogene (2013) 32, 1843–1853 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition V Coppola1,6, M Musumeci1,6, M Patrizii1, A Cannistraci1, A Addario1, M Maugeri-Sacca` 2, M Biffoni1, F Francescangeli1, M Cordenonsi3, S Piccolo3, L Memeo4, A Pagliuca1, G Muto5, A Zeuner1, R De Maria2,6 and D Bonci1,6 Prostate cancer is one of the leading causes of cancer-related death in men. Despite significant advances in prostate cancer diagnosis and management, the molecular events involved in the transformation of normal prostate cells into cancer cells have not been fully understood. It is generally accepted that prostate cancer derives from the basal compartment while expressing luminal markers. We investigated whether downregulation of the basal protein B-cell translocation gene 2 (BTG2) is implicated in prostate cancer transformation and progression. Here we show that BTG2 loss can shift normal prostate basal cells towards luminal markers expression, a phenotype also accompanied by the appearance of epithelial–mesenchymal transition (EMT) traits. We also show that the overexpression of microRNA (miR)-21 suppresses BTG2 levels and promotes the acquisition of luminal markers and EMT in prostate cells. Furthermore, by using an innovative lentiviral vector able to compete with endogenous mRNA through the overexpression of the 30-untranslated region of BTG2, we demonstrate that in prostate tumor cells, the levels of luminal and EMT markers can be reduced by derepression of BTG2 from microRNA-mediated control. -
A Deficiency in the Region Homologous to Human 17Q21.33
Copyright Ó 2006 by the Genetics Society of America DOI: 10.1534/genetics.105.054833 A Deficiency in the Region Homologous to Human 17q21.33–q23.2 Causes Heart Defects in Mice Y. Eugene Yu,*,†,1,2 Masae Morishima,‡ Annie Pao,* Ding-Yan Wang,§ Xiao-Yan Wen,§ Antonio Baldini*,‡,** and Allan Bradley††,1 *Department of Molecular and Human Genetics, ‡Department of Pediatrics (Cardiology), **Center for Cardiovascular Development, Baylor College of Medicine, Houston, Texas 77030, †Department of Cancer Genetics and Genetics Program, Roswell Park Cancer Institute, Buffalo, New York 14263, §Division of Cellular and Molecular Biology, Toronto General Research Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada and ††Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom Manuscript received December 17, 2005 Accepted for publication February 14, 2006 ABSTRACT Several constitutional chromosomal rearrangements occur on human chromosome 17. Patients who carry constitutional deletions of 17q21.3–q24 exhibit distinct phenotypic features. Within the deletion interval, there is a genomic segment that is bounded by the myeloperoxidase and homeobox B1 genes. This genomic segment is syntenically conserved on mouse chromosome 11 and is bounded by the mouse homologs of the same genes (Mpo and HoxB1). To attain functional information about this syntenic segment in mice, we have generated a 6.9-Mb deletion [Df(11)18], the reciprocal duplication [Dp(11)18] between Mpo and Chad (the chondroadherin gene), and a 1.8-Mb deletion between Chad and HoxB1. Phenotypic analyses of the mutant mouse lines showed that the Dp(11)18/Dp(11)18 genotype was responsible for embryonic or adolescent lethality, whereas the Df(11)18/1 genotype was responsible for heart defects. -
This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G
This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Expression and subcellular localisation of poly(A)-binding proteins Hannah Burgess PhD The University of Edinburgh 2010 Abstract Poly(A)-binding proteins (PABPs) are important regulators of mRNA translation and stability. In mammals four cytoplasmic PABPs with a similar domain structure have been described - PABP1, tPABP, PABP4 and ePABP. The vast majority of research on PABP mechanism, function and sub-cellular localisation is however limited to PABP1 and little published work has explored the expression of PABP proteins. Here, I examine the tissue distribution of PABP1 and PABP4 in mouse and show that both proteins differ markedly in their expression at both the tissue and cellular level, contradicting the widespread perception that PABP1 is ubiquitously expressed. PABP4 is shown to be widely expressed though with an expression pattern distinct from PABP1, and thus may have a biological function in many tissues.