DOCSLIB.ORG

Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Lubov T. Timchenko Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Edited by Lubov T. Timchenko Department of Medicine Baylor College of Medicine Houston, Texas, U.S.A. Kluwer Academic / Plenum Publishers New York, Boston, Dordrecht, London, Moscow Library of Congress Cataloging-in-Publication Data CIP applied for but not received at time of publication. Triplet Repeat Disorders of the Nervous System Edited by Lubov T. Timchenko ISBN 0-306-47417-4 AEMB volume number: 516 ©2002 Kluwer Academic / Plenum Publishers and Landes Bioscience Kluwer Academic / Plenum Publishers 233 Spring Street, New York, NY 10013 http://www.wkap.nl Landes Bioscience 810 S. Church Street, Georgetown, TX 78626 http://www.landesbioscience.com; http://www.eurekah.com Landes tracking number: 1-58706-055-8 10 987654321 A C.I.P. record for this book is available from the Library of Congress. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher. While the authors, editors and publisher believe that drug selection and dosage and the speci- fications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accu- mulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein. Printed in the United States of America. PREFACE World of Unstable Mutations The book “Triplet Repeat Diseases of the Nervous System” overviews the lat- est data on several disorders associated with unstable mutations. This field of re- search is progressing extremely fast. The number of polymorphic mutations and diseases caused by these mutations is increasing almost every month. There is a strong interest to molecular bases of triplet repeat disorders. This is explained by growing necessity to develop molecular approaches for cure of these diseases. There- fore, the authors of this book describe unstable mutations with the emphasis on molecular pathology. Broad discussion is presented on how polymorphic expan- sions cause cell dysfunction. • The first chapter of the book focuses on the molecular pathological pro- cesses that originate “unstable” mutations. The authors review several avail- able models by which normal “stable” region of DNA become pathogenic and discuss possible mechanisms causing DNA instability. • The other chapters of the book describe inherited diseases associated with different types of unstable mutations. Based on the location of mutation in the disease gene, polymorphic expansions of the nervous system can be divided into two major groups. First group includes disorders with unstable expansions within the open reading frame of the gene such as Spinocer- ebellar Ataxias caused by polyglutamine expansions. The second group in- cludes diseases caused by expansions situated within the untranslated re- gions of the gene. •In Chapter 3, the authors summarize comprehensive information (clinical, genetic, and molecular) on all known polyglutamine diseases with the em- phasis on the common and distinctive features between different disorders in this group. • Recent studies suggested that some Spinocerebellar Ataxias might be caused not by polyglutamine track, but by unstable repeats in untranslated regions of DNA. The authors in Chapter 4 discuss Spinocerebella Ataxia 10 that is associated with polymorphic ATTCT repeat in the intron of unknown gene. • The chapter 2 describes Myotonic Dystrophy 1 that is caused by unstable CTG repeats within the 3’ UTR of the disease gene. Multiple hypotheses v were proposed to explain this disease. The authors analyze several mouse models for DM1 disease and discuss how CTG repeat is expanded in pa- tients and why such expansion causes pathology. • Chapter 5 describes another example of disorder with polymorphic muta- tion in non coding region of the gene—Friedreich Ataxia. In this disease, GAA triplet repeat is located in the first intron of frataxin. The author pro- vides comprehensive information on clinical and genetic aspects of this disease and analyzes a variety of possible molecular pathways responsible for occurrence of mutation and development of pathology. What should we expect in future in this field? Identification of novel unstable mutations will be accompanied by identification of molecular pathways by which these mutations cause a disease. Emerging information from different fields of sci- ence (protein and RNA biology, physiology, crystallography, gene therapy, etc) will help to develop strategy to prevent and cure disorders with unstable mutations. The authors of this book are thankful to editorial coordinators and publishers for their support and tireless help. Lubov T. Timchenko Department of Medicine Baylor College of Medicine Houston, Texas, U.S.A. vi PARTICIPANTS Tetsuo Ashizawa Tohru Matsuura Department of Neurology Department of Neurology Baylor College of Medicine and Baylor College of Medicine and Veterans Affairs Medical Center Veterans Affairs Medical Center Houston, Texas 77030 Houston, Texas 77030 USA USA Alexis Brice Darren G. Monckton INSERM U289 Institute of Biomedical and Life Institut Fédératif di Recherche des Sciences Neurosciences The University of Glasgow Département de Génétique Glasgow, G12 8QQ Cytogénétique et Embryologie UK Groupe Hospitalier Pitié-Salpêtriére 75651 Paris Cédex 13 Massimo Pandolfo France Centre Hospitalier de la Université de Montréal Thomas A. Cooper Hopital Notre-Dame Departments of Pathology and 1560 rue Sherbrooke Est Molecular and Cell Biology Montréal, Quebec Baylor College of Medicine H2L 4M1 Canada Houston, TX 77030 USA Pawel Parniewski Centre for Microbiology and Virology Alexandra Dürr Polish Academy of Sciences INSERM U289 ul. Ludowa 106 Institut Fédératif di Recherche des 93-232 Lódz Neurosciences Poland Département de Génétique Cytogénétique et Embryologie Pawel Staczek Groupe Hospitalier Pitié-Salpêtriére Dept. of Genetics and Microorganisms 75651 Paris Cédex 13 University of Lódz France ul. Banacha 12/16 90-127 Lódz Poland vii viii Participants Giovanni Stevanin INSERM U289 Institut Fédératif di Recherche des Neurosciences Cytogénétique et Embryologie Groupe Hospitalier Pitié-Salpêtriére 75651 Paris Cédex 13 France Steve J. Tapscott Division of Human Biology Fred Hutchinson Research Center Seattle, WA 98109 USA Lubov T. Timchenko Section of Cardiovascular Sciences, Departments of Medicine, and Molecular Physiology & Biophysics Baylor College of Medicine Houston, TX 77030 USA CONTENTS 1. MOLECULAR MECHANISMS OF TRS INSTABILITY........................... 1 Pawel Parniewski and Pawel Staczek Introduction ......................................................................................................................... 1 Secondary DNA Structures as a Source of TRS Instability ............................................. 2 Summary ............................................................................................................................ 20 2. MYOTONIC DYSTROPHY: DISCUSSION OF MOLECULAR BASIS ......................................... 27 Lubov T. Timchenko, Steve J. Tapscott, Thomas A. Cooper and Darren G. Monckton DM1 Mutation is an Expansion of CTG Trinucleotide Repeats ................................... 27 Mouse Models of Unstable DNA ...................................................................................... 29 Molecular Pathogenesis of DM1 ....................................................................................... 31 Deficiency of Six5 in DM1 ................................................................................................. 34 Alterations of RNA Metabolism in DM1 ......................................................................... 35 CUGBP1 Targets ............................................................................................................... 39 Other Members of CUGBP1 Family ............................................................................... 39 Conclusions ........................................................................................................................ 40 3. SPINOCEREBELLAR ATAXIAS CAUSED BY POLYGLUTAMINE EXPANSIONS ........................................... 47 Giovanni Stevanin, Alexandra Dürr and Alexis Brice Polyglutamine Expansions as Major Mutations in ADCA ............................................ 49 Age at Onset ....................................................................................................................... 56 Clinical Presentation in Patients ...................................................................................... 56 Neuropathological Lesions ................................................................................................ 59 Factors Influencing Clinical Variability .......................................................................... 61 Physiopathology of Spinocerebellar ataxias Caused by Polyglutamine Expansions ... 61 Conclusions .......................................................................................................................
Load more

Recommended publications
  • Investigating the Role of Cdk11in Animal Cytokinesis
    Investigating the Role of CDK11 in Animal Cytokinesis by Thomas Clifford Panagiotou A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Molecular Genetics University of Toronto © Copyright by Thomas Clifford Panagiotou (2020) Investigating the Role of CDK11 in Animal Cytokinesis Thomas Clifford Panagiotou Master of Science Department of Molecular Genetics University of Toronto 2020 Abstract Finely tuned spatio-temporal regulation of cell division is required for genome stability. Cytokinesis constitutes the final stages of cell division, from chromosome segregation to the physical separation of cells, abscission. Abscission is tightly regulated to ensure it occurs after earlier cytokinetic events, like the maturation of the stem body, the regulatory platform for abscission. Active Aurora B kinase enforces the abscission checkpoint, which blocks abscission until chromosomes have been cleared from the cytokinetic machinery. Currently, it is unclear how this checkpoint is overcome. Here, I demonstrate that the cyclin-dependent kinase CDK11 is required for cytokinesis. Both inhibition and depletion of CDK11 block abscission. Furthermore, the mitosis-specific CDK11p58 kinase localizes to the stem body, where its kinase activity rescues the defects of CDK11 depletion and inhibition. These results suggest a model whereby CDK11p58 antagonizes Aurora B kinase to overcome the abscission checkpoint to allow for successful completion of cytokinesis. ii Acknowledgments I am very grateful for the support of my family and friends throughout my studies. I would also like to express my deep gratitude to Wilde Lab members, both past and present, for their advice and collaboration. In particular, I am very grateful to Matthew Renshaw, whose work comprises part of this thesis.
    [Show full text]
  • Support Info
    Electronic Supplementary Material (ESI) for RSC Advances. This journal is © The Royal Society of Chemistry 2014 Supporting Information Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C- 3’ side chains as potent Met kinase inhibitors Chia-Wei Liu,a Chun-Liang Lai,a Yu-Hsiang Lin,a Li-Wei Teng,a Sheng-chuan Yang,a Win-Yin Wei,a Shu Fu Lin,a Ju-Ying Yang,a Hung-Jyun Huang,a Ru-Wen Wang,a Chao-Cheng Chiang,a Mei-Hui Lee,a Yu- Chuan Wang,b Shih-Hsien Chuang,a Jia-Ming Chang,a Ying-Shuan E. Lee,a and Jiann-Jyh Huang*a,b aDevelopment Center for Biotechnology, No. 101, Lane 169, Kangning St., Xizhi District, New Taipei City 22180, Taiwan bDepartment of Applied Chemistry, National Chiayi University, No. 300, Syuefu Rd., Chiayi City 60004, Taiwan *Corresponding Author. Tel.: +886 5 271 7959; Fax: +886 5 271 7901. E-mail address: [email protected] (J.-J. Huang) Table of Contents: Page Supporting Figure. Ligplot diagrams of the ATP binding site of Met S2 complexed with compounds 2 and 20. Supporting Table. Kinase profiling data of compound 20. S3 References S10 - S1 - Supporting Figure. Ligplot diagrams1 of the ATP binding site of Met complexed with compounds 2 and 20: (A) Met with 2, and (B) Met with 20. - S2 - Supporting Table. Kinase profiling data of 20. Ambit KinomeScan Kinase Profiling (1.0 μM test concentration): Percentage of Percentage of Ambit Gene Symbol control (%) Ambit Gene Symbol control (%) 20 20 AAK1 68 ARK5 27 ABL1(E255K)-phosphorylated 85 ASK1 100 ABL1(F317I)-nonphosphorylated 78 ASK2 67
    [Show full text]
  • Profiling Data
    Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8
    [Show full text]
  • Genome-Wide Sirna Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib
    Published OnlineFirst May 11, 2010; DOI: 10.1158/0008-5472.CAN-09-4428 Published OnlineFirst on May 11, 2010 as 10.1158/0008-5472.CAN-09-4428 Integrated Systems and Technologies Cancer Research Genome-Wide siRNA Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib Siquan Chen1, Jonathan L. Blank2, Theodore Peters1, Xiaozhen J. Liu2, David M. Rappoli1, Michael D. Pickard3, Saurabh Menon1, Jie Yu2, Denise L. Driscoll2, Trupti Lingaraj2, Anne L. Burkhardt2, Wei Chen2, Khristofer Garcia1, Darshan S. Sappal2, Jesse Gray1, Paul Hales1, Patrick J. Leroy2, John Ringeling1, Claudia Rabino2, James J. Spelman2, Jay P. Morgenstern1, and Eric S. Lightcap2 Abstract Multiple pathways have been proposed to explain how proteasome inhibition induces cell death, but me- chanisms remain unclear. To approach this issue, we performed a genome-wide siRNA screen to evaluate the genetic determinants that confer sensitivity to bortezomib (Velcade (R); PS-341). This screen identified 100 genes whose knockdown affected lethality to bortezomib and to a structurally diverse set of other proteasome inhibitors. A comparison of three cell lines revealed that 39 of 100 genes were commonly linked to cell death. We causally linked bortezomib-induced cell death to the accumulation of ASF1B, Myc, ODC1, Noxa, BNIP3, Gadd45α, p-SMC1A, SREBF1, and p53. Our results suggest that proteasome inhibition promotes cell death primarily by dysregulating Myc and polyamines, interfering with protein translation, and disrupting essential DNA damage repair pathways, leading to programmed cell death. Cancer Res; 70(11); OF1–9. ©2010 AACR. Introduction active oxygen species (ROS), stabilization of Myc and Noxa, and induction of endoplasmic reticulum (ER) stress, any of The primary targets of most cancer chemotherapies are which may trigger cell death (1–4).
    [Show full text]
  • The Emerging Roles and Therapeutic Potential of Cyclin- Dependent Kinase 11 (CDK11) in Human Cancer
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 26 Review The emerging roles and therapeutic potential of cyclin- dependent kinase 11 (CDK11) in human cancer Yubing Zhou1,2, Jacson K. Shen2, Francis J. Hornicek2, Quancheng Kan1 and Zhenfeng Duan1,2 1 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China 2 Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, United States of America Correspondence to: Quancheng Kan, email: [email protected] Correspondence to: Zhenfeng Duan, email: [email protected] Keywords: CDK11, CDKs inhibitor, cell cycle, therapeutic target, cancer therapy Received: January 20, 2016 Accepted: March 28, 2016 Published: March 31, 2016 ABSTRACT Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment.
    [Show full text]
  • Androgen Receptor
    RALTITREXED Dihydrofolate reductase BORTEZOMIB IsocitrateCannabinoid dehydrogenase CB1EPIRUBICIN receptor HYDROCHLORIDE [NADP] cytoplasmic VINCRISTINE SULFATE Hypoxia-inducible factor 1 alpha DOXORUBICINAtaxin-2 HYDROCHLORIDENIFENAZONEFOLIC ACID PYRIMETHAMINECellular tumor antigen p53 Muscleblind-likeThyroidVINBURNINEVINBLASTINETRIFLURIDINE protein stimulating 1 DEQUALINIUM SULFATEhormone receptor CHLORIDE Menin/Histone-lysine N-methyltransferasePHENELZINE MLLLANATOSIDE SULFATE C MELATONINDAUNORUBICINBETAMETHASONEGlucagon-like HYDROCHLORIDEEndonuclease peptide 4 1 receptor NICLOSAMIDEDIGITOXINIRINOTECAN HYDROCHLORIDE HYDRATE BISACODYL METHOTREXATEPaired boxAZITHROMYCIN protein Pax-8 ATPase family AAA domain-containing proteinLIPOIC 5 ACID, ALPHA Nuclear receptorCLADRIBINEDIGOXIN ROR-gammaTRIAMTERENE CARMUSTINEEndoplasmic reticulum-associatedFLUOROURACIL amyloid beta-peptide-binding protein OXYPHENBUTAZONEORLISTAT IDARUBICIN HYDROCHLORIDE 6-phospho-1-fructokinaseHeat shockSIMVASTATIN protein beta-1 TOPOTECAN HYDROCHLORIDE AZACITIDINEBloom syndromeNITAZOXANIDE protein Huntingtin Human immunodeficiency virus typeTIPRANAVIR 1 protease VitaminCOLCHICINE D receptorVITAMIN E FLOXURIDINE TAR DNA-binding protein 43 BROMOCRIPTINE MESYLATEPACLITAXEL CARFILZOMIBAnthrax lethalFlap factorendonucleasePrelamin-A/C 1 CYTARABINE Vasopressin V2 receptor AMITRIPTYLINEMicrotubule-associated HYDROCHLORIDERetinoidTRIMETHOPRIM proteinMothers X receptor tau against alpha decapentaplegic homolog 3 Histone-lysine N-methyltransferase-PODOFILOX H3 lysine-9OXYQUINOLINE
    [Show full text]
  • ABBOTT MOLECULAR ONCOLOGY and GENETICS 2015-2016 Product Catalog
    DESCRIPTOR, 9/12, ALL CAPS ABBOTT MOLECULAR ONCOLOGY AND GENETICS 2015-2016 Product Catalog Area for placed imagery Only use imagery that is relevant to the communication CHOOSE TRANSFORMATION See where it will take you at AbbottMolecular.com 2 Please note some products may not be for sale in all markets. Contact your local representative for availability. ASR (Analyte Specific Reagent) Analytical and performance characteristics are not established CE (CE Marked) Conformité Européenne GPR (General Purpose Reagent) For Laboratory use RUO (Research Use Only) Not for use in diagnostic procedures All products manufactured and/or distributed by Abbott Molecular should be used in accordance with the products’ labeled intended use. Products labeled “Research Use Only” should be used for research applications, and are not for use in diagnostic procedures. CEP, LSI, AneuVysion, MultiVysion, PathVysion and Vysis are registered trademarks of Vysis, Inc., AutoVysion, ProbeChek, SpectrumAqua, SpectrumBlue, SpectrumGreen, SpectrumGold, SpectrumOrange, SpectrumRed, TelVysion, ToTelVysion, UroVysion and VP 2000 are trademarks of Abbott Molecular in various jurisdictions. All other trademarks are the property of their respective owners. Please note some products may not be for sale in all markets. Contact your local representative for availability. 3 Abbott Molecular is Transforming Laboratory Partnerships and Productivity—Today and into the Future As a leader in molecular Our commitment to exploring new clinical frontiers is evident in the development and delivery of innovative diagnostics, Abbott is committed systems and assay solutions that aid physicians in the diagnosis of disease, selection of therapies and monitoring to providing solution-oriented of disease. offerings built on FISH and PCR.
    [Show full text]
  • The Emerging Role of Cyclin-Dependent Kinases (Cdks) in Pancreatic Ductal Adenocarcinoma
    International Journal of Molecular Sciences Review The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma Balbina García-Reyes 1,†, Anna-Laura Kretz 1,†, Jan-Philipp Ruff 1, Silvia von Karstedt 2,3, Andreas Hillenbrand 1, Uwe Knippschild 1, Doris Henne-Bruns 1 and Johannes Lemke 1,* 1 Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; [email protected] (B.G.-R.); [email protected] (A.-L.K.); [email protected] (J.-P.R.); [email protected] (A.H.); [email protected] (U.K.); [email protected] (D.H.-B.) 2 Department of Translational Genomics, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany; [email protected] 3 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany * Correspondence: [email protected]; Tel.: +49-731-500-53961 † These authors contributed equally to this work. Received: 31 August 2018; Accepted: 11 October 2018; Published: 18 October 2018 Abstract: The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.
    [Show full text]
  • Cdks in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets
    International Journal of Molecular Sciences Review CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets Jordan L Kohlmeyer 1,2, David J Gordon 3 , Munir R Tanas 4, Varun Monga 5 , Rebecca D Dodd 5 and Dawn E Quelle 1,2,4,* 1 Molecular Medicine Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; [email protected] 2 The Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, 2-570 Bowen Science Bldg., Iowa City, IA 52242, USA 3 The Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; [email protected] 4 The Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; [email protected] 5 The Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; [email protected] (V.M.); [email protected] (R.D.D.) * Correspondence: [email protected]; Tel.: +319-353-5749; Fax: +319-335-8930 Received: 6 April 2020; Accepted: 22 April 2020; Published: 24 April 2020 Abstract: Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood.
    [Show full text]
  • Cyclin-Dependent Kinase 11 (CDK11)
    Published OnlineFirst May 20, 2016; DOI: 10.1158/1535-7163.MCT-16-0032 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics Cyclin-Dependent Kinase 11 (CDK11) Is Required for Ovarian Cancer Cell Growth In Vitro and In Vivo, and Its Inhibition Causes Apoptosis and Sensitizes Cells to Paclitaxel Xianzhe Liu1,2, Yan Gao1, Jacson Shen1, Wen Yang1,3, Edwin Choy1, Henry Mankin1, Francis J. Hornicek1, and Zhenfeng Duan1 Abstract Ovarian cancer is currently the most lethal gynecologic compared with the matched, original primary tumors. RNAi- malignancy with limited treatment options. Improved tar- mediated CDK11 silencing by synthetic siRNA or lentiviral geted therapies are needed to combat ovarian cancer. Here, shRNA decreased cell proliferation and induced apoptosis in we report the identification of cyclin-dependent kinase 11 ovarian cancer cells. Moreover, CDK11 knockdown enhances (CDK11) as a mediator of tumor cell growth and proliferation the cytotoxic effect of paclitaxel to inhibit cell growth in in ovarian cancer cells. Although CDK11 has not been impli- ovarian cancer cells. Systemic in vivo administration of CDK11 cated previously in this disease, we have found that its expres- siRNA reduced the tumor growth in an ovarian cancer xeno- sion is upregulated in human ovarian cancer tissues and graft model. Our findings suggest that CDK11 may be a associated with malignant progression. Metastatic and recur- promising therapeutic target for the treatment of ovarian rent tumors have significantly higher CDK11 expression when cancer patients. Mol Cancer Ther; 15(7); 1691–701. Ó2016 AACR. Introduction stagnant at approximately 45% (6). Therefore, there is an urgent need to develop novel targeted therapies to improve the treatment Ovarian cancer is currently the most lethal gynecologic malig- of ovarian cancer.
    [Show full text]
  • Lestaurtinib
    LESTAURTINIB MIDOSTAURIN AXITINIB Tyrosine-protein kinase TIE-2 Serine/threonine-protein kinase 2Mitogen-activated protein kinase kinase kinase kinase 5 Serine/threonine-protein kinase MST2 NERATINIB SPS1/STE20-related protein kinase YSK4 SORAFENIB Dual specificity mitogen-activated protein kinase kinase 5 Proto-oncogene tyrosine-protein kinase MER Platelet-derivedTANDUTINIB growth factor receptor beta Epithelial discoidin domain-containing receptor 1 NINTEDANIB Mixed lineage kinase 7 Macrophage colonyTyrosine-protein stimulating kinasefactor receptorreceptor UFOTyrosine-protein kinase BLK Tyrosine-protein kinase LCK NILOTINIB Serine/threonine-protein kinase 10 NT-3 growth factor receptor DiscoidinMitogen-activated domain-containing protein receptor kinase 2 kinase kinase kinase 3 Tyrosine-protein kinase ABL Nerve growth factor receptor Trk-A FORETINIBEphrin type-B receptor 6 Adaptor-associated kinaseQUIZARTINIB Ephrin type-AEphrin receptor type-B receptor5 2 Mitogen-activated proteinTyrosine-protein kinase kinase kinaseTyrosine-protein kinase JAK3 kinase 2 kinase receptor FLT3 Fibroblast growth factorSerine/threonine-protein receptor 1 kinase Aurora-B Ephrin type-A receptor 8 Serine/threonine-proteinDual specificty protein kinase kinase PLK4Mitogen-activated CLK1 protein kinase kinase kinase 12 Misshapen-like kinase 1Cyclin-dependent kinase-like 2 Platelet-derivedLINIFANIB growth factor receptorEphrin alpha type-A receptor 4 c-Jun N-terminal kinaseALISERTIB 3 Serine/threonine-protein kinase SIK1 PONATINIB Dual specificity protein kinaseStem
    [Show full text]
  • Site-Specific Regulation of Cell Cycle and DNA Repair in Post-Mitotic GABA Cells in Schizophrenic Versus Bipolars
    Correction NEUROSCIENCE RPA3, the fold change (+ 1.35) should be printed in red color Correction for “Site-specific regulation of cell cycle and DNA font instead of blue color font. On page 11732, right column, repair in post-mitotic GABA cells in schizophrenic versus bipo- third paragraph, ninth line, “The replication protein (RPA3), lars,” by Francine M. Benes, Benjamin Lim, and Sivan Sub- Proc Natl which interacts directly with p53 in the setting of DNA damage buraju, which appeared in issue 28, July 14, 2009, of fi ” Acad Sci USA fi (11), was also signi cantly decreased in expression, should in- (106:11731-11736; rst published June 29, 2009; “ 10.1073/pnas.0903066106). stead appear as, The replication protein (RPA3), which inter- The authors note that in Figure 1, CA3/2 Bipolar Disorder, acts directly with p53 in the setting of DNA damage (11), was “Replication protein” was printed in blue color font, but instead also significantly increased in expression.” This error does not should be printed in red. In Table 1, CA3/2 stratum oriens affect the conclusions of the article. The corrected figure and (bipolar disorder) in the section (DNA Damage Response) table and their legends appear below. Fig 1. The regulation of G1/S and G2/M phase in GABA cells of the stratum oriens (SO) in CA3/2 and CA1 of schizophrenics (SZs; left upper and lower panels) and bipolars (BDs; right upper and lower panels). In each of the diagrams, he G1/S and G2/M phases of cell cycle and their associated genes are shown.
    [Show full text]