Regulation of Local Translation, Synaptic Plasticity, and Cognitive Function by CNOT7
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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. -
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. -
A Study on Acute Myeloid Leukemias with Trisomy 8, 11, Or 13, Monosomy 7, Or Deletion 5Q
Leukemia (2005) 19, 1224–1228 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q C Schoch1, A Kohlmann1, M Dugas1, W Kern1, W Hiddemann1, S Schnittger1 and T Haferlach1 1Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany We performed microarray analyses in AML with trisomies 8 aim of this study to investigate whether gains and losses on the (n ¼ 12), 11 (n ¼ 7), 13 (n ¼ 7), monosomy 7 (n ¼ 9), and deletion genomic level translate into altered genes expression also in 5q (n ¼ 7) as sole changes to investigate whether genomic gains and losses translate into altered expression levels of other areas of the genome in AML. genes located in the affected chromosomal regions. Controls were 104 AML with normal karyotype. In subgroups with trisomy, the median expression of genes located on gained Materials and methods chromosomes was higher, while in AML with monosomy 7 and deletion 5q the median expression of genes located in deleted Samples regions was lower. The 50 most differentially expressed genes, as compared to all other subtypes, were equally distributed Bone marrow samples of AML patients at diagnosis were over the genome in AML subgroups with trisomies. In contrast, 30 and 86% of the most differentially expressed genes analyzed: 12 cases with trisomy 8 (AML-TRI8), seven with characteristic for AML with 5q deletion and monosomy 7 are trisomy 11 (AML-TRI11), seven with trisomy 13 (AML-TRI13), located on chromosomes 5 or 7. -
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. -
BTG2 Bridges PABPC1 RNA-Binding Domains and CAF1 Deadenylase to Control Cell Proliferation
ARTICLE Received 21 May 2015 | Accepted 24 Jan 2016 | Published 25 Feb 2016 DOI: 10.1038/ncomms10811 OPEN BTG2 bridges PABPC1 RNA-binding domains and CAF1 deadenylase to control cell proliferation Benjamin Stupfler1,2,3,4, Catherine Birck1,2,3,4, Bertrand Se´raphin1,2,3,4 & Fabienne Mauxion1,2,3,4 While BTG2 plays an important role in cellular differentiation and cancer, its precise molecular function remains unclear. BTG2 interacts with CAF1 deadenylase through its APRO domain, a defining feature of BTG/Tob factors. Our previous experiments revealed that expression of BTG2 promoted mRNA poly(A) tail shortening through an undefined mechanism. Here we report that the APRO domain of BTG2 interacts directly with the first RRM domain of the poly(A)-binding protein PABPC1. Moreover, PABPC1 RRM and BTG2 APRO domains are sufficient to stimulate CAF1 deadenylase activity in vitro in the absence of other CCR4–NOT complex subunits. Our results unravel thus the mechanism by which BTG2 stimulates mRNA deadenylation, demonstrating its direct role in poly(A) tail length control. Importantly, we also show that the interaction of BTG2 with the first RRM domain of PABPC1 is required for BTG2 to control cell proliferation. 1 Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, 67404 Illkirch, France. 2 Centre National de la Recherche Scientifique UMR7104, 67404 Illkirch, France. 3 Institut National de la Sante´ et de la Recherche Me´dicale U964, 67404 Illkirch, France. 4 Universite´ de Strasbourg, 67404 Illkirch, France. Correspondence and requests for materials should be addressed to B.Se. (email: [email protected]) or to F.M. -
Tob2 Phosphorylation Regulates Global Mrna Turnover to Reshape Transcriptome and Impact Cell Proliferation
Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Research Article (Revised) Tob2 phosphorylation regulates global mRNA turnover to reshape transcriptome and impact cell proliferation Chyi-Ying A. Chen1, Krista Strouz1, Kai-Lieh Huang1, 2, and Ann-Bin Shyu1, * 1Department of Biochemistry and Molecular Biology, McGovern Medical School The University of Texas Health Science Center at Houston, Houston, Texas 77030 Running Title: Tob2-promoted deadenylation reshapes transcriptome Keywords: mRNA turnover, deadenylation, transcriptome programming, PABP interaction, Ccr4-Not complex, phosphorylation 2Current Address: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, Texas 77550 *Corresponding author: Tel: (713) 500-6068; Fax: (713) 500-0652; E-mail address: Ann- [email protected]. Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract Tob2, an anti-proliferative protein, promotes deadenylation through recruiting Caf1 deadenylase to the mRNA poly(A) tail by simultaneously interacting with both Caf1 and poly(A)-binding protein (PABP). Previously, we found that changes in Tob2 phosphorylation can alter its PABP- binding ability and deadenylation-promoting function. However, it remained unknown regarding the relevant kinase(s). Moreover, it was unclear whether Tob2 phosphorylation modulates the transcriptome and whether the phosphorylation is linked to Tob2’s anti-proliferative function. In this study, we found that c-Jun N-terminal kinase (JNK) increases phosphorylation of Tob2 at many Ser/Thr sites in the intrinsically disordered region (IDR) that contains two separate PABP- interacting PAM2 motifs. JNK-induced phosphorylation or phosphomimetic mutations at these sites weaken the Tob2-PABP interaction. -
Novelty Indicator for Enhanced Prioritization of Predicted Gene Ontology Annotations
IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. X, NO. X, MONTHXXX 20XX 1 Novelty Indicator for Enhanced Prioritization of Predicted Gene Ontology Annotations Davide Chicco, Fernando Palluzzi, and Marco Masseroli Abstract—Biomolecular controlled annotations have become pivotal in computational biology, because they allow scientists to analyze large amounts of biological data to better understand their test results, and to infer new knowledge. Yet, biomolecular annotation databases are incomplete by definition, like our knowledge of biology, and may contain errors and inconsistent information. In this context, machine-learning algorithms able to predict and prioritize new biomolecular annotations are both effective and efficient, especially if compared with the time-consuming trials of biological validation. To limit the possibility that these techniques predict obvious and trivial high-level features, and to help prioritizing their results, we introduce here a new element that can improve the accuracy and relevance of the results of an annotation prediction and prioritization pipeline. We propose a novelty indicator able to state the level of ”newness” (or ”originality”) of the annotations predicted for a specific gene to Gene Ontology terms, and to help prioritizing the most novel and interesting annotations predicted. We performed a thorough biological functional analysis of the prioritized annotations predicted with high accuracy by using this indicator and our previously proposed prediction algorithms. The relevance -
Transcriptome Analysis of Different Multidrug-Resistant Gastric Carcinoma Cells
in vivo 19: 583-590 (2005) Transcriptome Analysis of Different Multidrug-resistant Gastric Carcinoma Cells STEFFEN HEIM1 and HERMANN LAGE2 1Europroteome AG, Berlin-Hennigsdorf; 2Institute of Pathology, Charité Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany Abstract. Multidrug resistance (MDR) of human cancers is advanced cancer. These therapeutic protocols produce an the major cause of failure of chemotherapy. To better overall response rate of about 20% at best using a single- understand the molecular events associated with the agent, and up to 50% using combination chemotherapy. development of different types of MDR, two different multidrug- Thus, a large number of malignancies are incurable. resistant gastric carcinoma cell lines, the MDR1/P-glycoprotein- Generally, gastrointestinal cancers, including gastric expressing cell line EPG85-257RDB and the MDR1/P- carcinoma, are naturally resistant to many anticancer drugs. glycoprotein-negative cell variant EPG85-257RNOV, as well as Additionally, these tumors are able to develop acquired the corresponding drug-sensitive parental cell line EPG85-257P, drug resistance phenotypes, which include the multidrug were used for analyses of the mRNA expression profiles by resistance (MDR) phenomenon. cDNA array hybridization. Of more than 12,000 genes spotted The MDR phenotype is characterized by simultaneous on the arrays, 156 genes were detected as being significantly resistance of tumor cells to various antineoplastic agents regulated in the cell line EPG85-257RDB in comparison to the which are structurally and functionally unrelated. Besides non-resistant cell variant, and 61 genes were found to be the classical MDR phenotype, mediated by the enhanced differentially expressed in the cell line EPG85-257RNOV. -
Mechanism of Translation Regulation of BTG1 by Eif3 Master's Thesis
Mechanism of Translation Regulation of BTG1 by eIF3 Master’s Thesis Presented to The Faculty of the Graduate School of Arts and Sciences Brandeis University Department of Biology Amy S.Y. Lee, Advisor In Partial Fulfillment of the Requirements for the Degree Master of Science in Biology by Shih-Ming (Annie) Huang May 2019 Copyright by Shih-Ming (Annie) Huang © 2019 ACKNOWLEDGEMENT I would like to express my deepest gratitude to Dr. Amy S.Y. Lee for her continuous patience, support, encouragement, and guidance throughout this journey. I am very thankful for all the members of the Lee Lab for providing me with this caring and warm environment to complete my work. I would also like to thank Dr. James NuñeZ for collaborating with us on this project and helping us in any shape or form. iii ABSTRACT Mechanism of Translation Regulation of BTG1 by eIF3 A thesis presented to the Department of Biology Graduate School of Arts and Sciences Brandeis University Waltham, Massachusetts By Shih-Ming (Annie) Huang REDACTED iv TABLE OF CONTENTS REDACTED v LIST OF FIGURES REDACTED vi INTRODUCTION I. Gene Regulation All cells in our bodies contain the same genome, but distinct cell types express very different sets of genes. The sets of gene expressed under specific conditions determine what the cell can do, by controlling the proteins and functional RNAs the cell contains. The process of controlling which genes are expressed is known as gene regulation. Any step along the gene expression pathway can be controlled, from DNA transcription, translation of mRNAs into proteins, to post-translational modifications. -
Structural and Functional Studies of Mrna Stability Regulators
Research Collection Doctoral Thesis Structural and Functional Studies of mRNA Stability Regulators Author(s): Ripin, Nina Publication Date: 2018-11 Permanent Link: https://doi.org/10.3929/ethz-b-000303696 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 25327 Structural and functional studies of mRNA stability regulators A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZÜRICH (Dr. sc. ETH Zürich) presented by NINA RIPIN Diplom-Biochemikerin, Goethe University, Frankfurt, Germany Born on 06.08.1986 citizen of Germany accepted on the recommendation of Prof. Dr. Frédéric Allain Prof. Dr. Stefanie Jonas Prof. Dr. Michael Sattler Prof. Dr. Witold Filipowicz 2018 “Success consists of going from failure to failure without loss of enthusiasm.” Winston Churchill Summary Posttranscriptional gene regulation (PTGR) is the process by which every step of the life cycle of an mRNA following transcription – maturation, transport, translation, subcellular localization and decay - is tightly regulated. This is accomplished by a complex network of multiple RNA binding proteins (RNPs) binding to several specific mRNA elements. Such cis-acting elements are or can be found within the 5’ cap, the 5’ untranslated region (UTR), the open reading frame (ORF), the 3’UTR and the poly(A) tail at the 3’ end of the mRNA. Adenylate-uridylate-rich elements (AU-rich elements; AREs) are heavily investigated regulatory cis- acting elements within 3’untranslated regions (3’UTRs). These are found in short-lived mRNAs and function as a signal for rapid degradation. -
Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author J Bone Miner Manuscript Author Res. Author Manuscript Author manuscript; available in PMC 2019 July 23. Published in final edited form as: J Bone Miner Res. 2019 July ; 34(7): 1284–1296. doi:10.1002/jbmr.3698. Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry A full list of authors and affiliations appears at the end of the article. Abstract Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ~2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10−8) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. -
Importance of CNOT8 Deadenylase Subunit in DNA Damage Responses Following Ionizing Radiation (IR)
Reports of Biochemistry & Molecular Biology Vol.9, No.1, July 2020 Original article www.RBMB.net Importance of CNOT8 Deadenylase Subunit in DNA Damage Responses Following Ionizing Radiation (IR) Samira Eskandarian1,2, Roger Grand2, Shiva Irani*1, Mohsen Saeedi3, Reza Mirfakhraie4 Abstract Background: The Ccr4-Not protein complex (CNOT complex) is a key regulator of gene expression in eukaryotic cells. Ccr4-Not Complex is composed of at least nine conserved subunits in mammalian cells with two main enzymatic activities. CNOT8 is a subunit of the complex with deadenylase activity that interacts transiently with the CNOT6 or CNOT6L subunits. Here, we focused on the role of the human CNOT8 subunit in the DNA damage response (DDR). Methods: Cell viability was assessed to measure ATP level using a Cell Titer-Glo Luminescence reagent up to 4 days’ post CNOT8 siRNA transfection. In addition, expression level of phosphorylated proteins in signalling pathways were detected by western blotting and immunofluorescence microscopy. CNOT8- depleted Hela cells post- 3 Gy ionizing radiation (IR) treatment were considered as a control. Results: Our results from cell viability assays indicated a significant reduction at 72-hour post CNOT8 siRNA transfection (p= 0.04). Western blot analysis showed slightly alteration in the phosphorylation of DNA damage response (DDR) proteins in CNOT8-depleted HeLa cells following treatment with ionizing radiation (IR). Increased foci formation of H2AX, RPA, 53BP1, and RAD51 foci was observed after IR in CNOT8-depleted cells compared to the control cells. Conclusions: We conclude that CNOT8 deadenylase subunit is involved in the cellular response to DNA damage. Keywords: CNOT complex, CNOT8, DNA damage response, SiRNA.