The Ubiquitin System for Protein Degradation and Some of Its Roles in the Control of the Cell Division Cycle*
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Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking
Cells 2014, 3, 1027-1088; doi:10.3390/cells3041027 OPEN ACCESS cells ISSN 2073-4409 www.mdpi.com/journal/cells Review Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking Zoi Erpapazoglou 1,2, Olivier Walker 3 and Rosine Haguenauer-Tsapis 1,* 1 Institut Jacques Monod-CNRS, UMR 7592, Université-Paris Diderot, Sorbonne Paris Cité, F-75205 Paris, France; E-Mail: [email protected] 2 Current address: Brain and Spine Institute, CNRS UMR 7225, Inserm, U 1127, UPMC-P6 UMR S 1127, 75013 Paris, France 3 Institut des Sciences Analytiques, UMR5280, Université de Lyon/Université Lyon 1, 69100 Villeurbanne, France; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]. External Editor: Hanjo Hellmann Received: 14 July 2014; in revised form: 14 October 2014 / Accepted: 21 October 2014 / Published: 12 November 2014 Abstract: Modification by Lys63-linked ubiquitin (UbK63) chains is the second most abundant form of ubiquitylation. In addition to their role in DNA repair or kinase activation, UbK63 chains interfere with multiple steps of intracellular trafficking. UbK63 chains decorate many plasma membrane proteins, providing a signal that is often, but not always, required for their internalization. In yeast, plants, worms and mammals, this same modification appears to be critical for efficient sorting to multivesicular bodies and subsequent lysosomal degradation. UbK63 chains are also one of the modifications involved in various forms of autophagy (mitophagy, xenophagy, or aggrephagy). Here, in the context of trafficking, we report recent structural studies investigating UbK63 chains assembly by various E2/E3 pairs, disassembly by deubiquitylases, and specifically recognition as sorting signals by receptors carrying Ub-binding domains, often acting in tandem. -
Springer A++ Viewer
PublisherInfo PublisherName : BioMed Central PublisherLocation : London PublisherImprintName : BioMed Central Ubiquitin researchers win Nobel ArticleInfo ArticleID : 5007 ArticleDOI : 10.1186/gb-spotlight-20041007-02 ArticleCitationID : spotlight-20041007-02 ArticleSequenceNumber : 70 ArticleCategory : Research news ArticleFirstPage : 1 ArticleLastPage : 3 RegistrationDate : 2004–10–7 ArticleHistory : OnlineDate : 2004–10–7 ArticleCopyright : BioMed Central Ltd2004 ArticleGrants : ArticleContext : 130595511 Stephen Pincock Email: [email protected] Three researchers who made fundamental breakthroughs in understanding ubiquitin-mediated proteolysis have been awarded the 2004 Nobel Prize in Chemistry, the Royal Swedish Academy of Sciences said on Wednesday (October 6). Aaron Ciechanover and Avram Hershko, from the Israel Institute of Technology, Haifa, and Irwin Rose, of the University of California, Irvine, will share the prize for their discoveries in the 1970s and 1980s that began to reveal the central role of the tiny 76-amino acid protein in numerous cellular processes. "Thanks to the work of the three laureates, it is now possible to understand at a molecular level how the cell controls a number of central processes by breaking down certain proteins and not others," the academy said. "Without doubt they deserve this prize," John Mayer, professor of molecular cell biology at the University of Nottingham, told us. "Protein modification by ubiquitylation is just as important as protein phosphorylation for what goes on in the cell." Ubiquitin-mediated protein degradation governs processes as varied as cell division, DNA repair, quality control of newly produced proteins, and parts of the immune system. Problems with the ubiquitin–proteosome system are implicated in human diseases including cervical cancer and cystic fibrosis. "The reason they've got this Nobel Prize is because ubiquitin is attached to proteins in different ways not only for degradation, but also to make other things happen in the cell," Mayer added. -
PGC-1A Protects from Notch-Induced Kidney Fibrosis Development
BASIC RESEARCH www.jasn.org PGC-1a Protects from Notch-Induced Kidney Fibrosis Development † ‡ ‡ Seung Hyeok Han,* Mei-yan Wu, § Bo Young Nam, Jung Tak Park,* Tae-Hyun Yoo,* ‡ † † † † Shin-Wook Kang,* Jihwan Park, Frank Chinga, Szu-Yuan Li, and Katalin Susztak *Department of Internal Medicine, Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea; †Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ‡Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University College of Medicine, Seoul, Korea; and §Department of Nephrology, The First Hospital of Jilin University, Changchun, China ABSTRACT Kidney fibrosis is the histologic manifestation of CKD. Sustained activation of developmental pathways, such as Notch, in tubule epithelial cells has been shown to have a key role in fibrosis development. The molecular mechanism of Notch-induced fibrosis, however, remains poorly understood. Here, we show that, that expression of peroxisomal proliferation g-coactivator (PGC-1a) and fatty acid oxidation-related genes are lower in mice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/ICN1) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene Hes1 directly binds to the regulatory region of PGC-1a. Compared with Pax8-rtTA/ICN1 transgenic animals, Pax8-rtTA/ICN1/Ppargc1a transgenic mice showed improvement of renal structural alterations (on his- tology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1a restored mi- tochondrial content and reversed the fatty acid oxidation defect induced by Notch overexpression in vitro in tubule cells. Furthermore, compared with Pax8-rtTA/ICN1 mice, Pax8-rtTA/ICN1/Ppargc1a mice exhibited improvement in renal fatty acid oxidation gene expression and apoptosis. -
Ubiquitin-Mediated Proteolysis the Nobel Prize in Chemistry for 2004 Is
Advanced information on the Nobel Prize in Chemistry, 6 October 2004 Information Department, P.O. Box 50005, SE-104 05 Stockholm, Sweden Phone: +46 8 673 95 00, Fax: +46 8 15 56 70, E-mail: [email protected], Website: www.kva.se Ubiquitin-mediated proteolysis The Nobel Prize in Chemistry for 2004 is shared between three scientists who have made fundamental discoveries concerning how cells regulate the breakdown of intracellular proteins with extreme specificity as to target, time and space. Aaron Ciechanover, Avram Hershko and Irwin Rose together discovered ubiquitin- mediated proteolysis, a process where an enzyme system tags unwanted proteins with many molecules of the 76-amino acid residue protein ubiquitin. The tagged proteins are then transported to the proteasome, a large multisubunit protease complex, where they are degraded. Numerous cellular processes regulated by ubiquitin-mediated proteolysis include the cell cycle, DNA repair and transcription, protein quality control and the immune response. Defects in this proteolysis have a causal role in many human diseases, including a variety of cancers. Fig. 1 Ubiquitin-mediated proteolysis and its many biological functions 2 Introduction Eukaryotic cells, from yeast to human, contain some 6000 to 30000 protein-encoding genes and at least as many proteins. While much attention and research had been devoted to how proteins are synthesized, the reverse process, i.e. how proteins are degraded, long received little attention. A pioneer in this field was Schoenheimer, who in 1942 published results from isotope tracer techniques indicating that proteins in animals are continuously synthesized and degraded and therefore are in a dynamic state (Schoenheimer, 1942). -
The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression
International Journal of Molecular Sciences Review The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression Tingting Zou and Zhenghong Lin * School of Life Sciences, Chongqing University, Chongqing 401331, China; [email protected] * Correspondence: [email protected] Abstract: The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), which activities are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins, CDK inhibitors (CKIs), other kinases and phosphatases. Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell cycle progression via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor or abnormally high accumulation of oncoproteins often results in deregulation of cell proliferation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the regulation of UPS machinery of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell cycle transition, cancer treatment, and the development of anti-cancer drugs. Keywords: cell cycle regulation; CDKs; cyclins; CKIs; UPS; E3 ubiquitin ligases; Deubiquitinases (DUBs) Citation: Zou, T.; Lin, Z. The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression. 1. Introduction Int. J. Mol. Sci. 2021, 22, 5754. https://doi.org/10.3390/ijms22115754 The cell cycle is a ubiquitous, complex, and highly regulated process that is involved in the sequential events during which a cell duplicates its genetic materials, grows, and di- Academic Editors: Kwang-Hyun Bae vides into two daughter cells. -
Folding, Function and Subcellular Localization of Parkin
Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universtität München Folding, function and subcellular localization of parkin Julia Schlehe aus München 2008 Erklärung Diese Dissertation wurde im Sinne von §13 Abs. 3 der Promotionsordnung vom 29. Januar 1998 von PD Dr. Winklhofer betreut. Ehrenwörtliche Versicherung Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet. München, am 07.10.2008 …………………………………….. (Julia Schlehe) Dissertation eingereicht am 09.10.2008 1. Gutachter PD Dr. Konstanze Winklhofer 2. Gutachter Prof. Dr. Ulrich Hartl Mündliche Prüfung am 10.11.2008 Summary ...............................................................................................................................................................1 Introduction ..........................................................................................................................................................3 Parkinson’s Disease........................................................................................................................................3 History......................................................................................................................................................3 Clinical characteristics, symptoms and treatment ....................................................................................4 Neuropathological characteristics ............................................................................................................6 -
1 the Functional Interplay Between the HIF Pathway and the Ubiquitin System
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 The functional interplay between the HIF pathway and the ubiquitin system – more than a one-way road Günter, Julia ; Ruiz-Serrano, Amalia ; Pickel, Christina ; Wenger, Roland H ; Scholz, Carsten C Abstract: The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue func- tions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIF subunits leads to the recruitment ofan E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIF subunits, demonstrating the regulation of the HIF pathway by the ubiq- uitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the beststudied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway. -
Proteasome Inhibitors in Cancer Therapy: Death by Indigestion
Cell Death and Differentiation (2005) 12, 1255–1257 & 2005 Nature Publishing Group All rights reserved 1350-9047/05 $30.00 www.nature.com/cdd Book Review Proteasome inhibitors in cancer therapy: death by indigestion M Rossi1, A Oberst2, A Emre Sayan1 and P Salomoni*,1 1 MRC, Toxicology Unit, Leicester, UK; 2 IDI-IRCCS Biochemistry Lab, c/o University of Rome Tor Vergata, Rome, Italy * Corresponding author. P Salomoni. E-mail: [email protected] Cell Death and Differentiation (2005) 12, 1255–1257. doi:10.1038/sj.cdd.4401701 Proteasome Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. By J Adams. Humana Press, Totowa, New Jersey: 2004. pp 312. ISBN: 1-58829-250-9 As Eugene Garfield said, while it is easy to recognize a good same issue containing manuscripts from scientists that have paper, it could be more difficult to recognize a bad paper. In originated in this field.7–10 fact, the results could be weak, but the conclusion could still For those of us engaged in basic research in the field be right, even though not fully supported by the data shown. of cancer and apoptosis, the hope that our work might, in Preliminary reports could also fall in this category. After some small way and at some future juncture, contribute to all, it was not a Cell but a BBRC paper – only a little BBRC of the clinical treatment of human cancers is a major motivator. three impact factor – describing a novel experimental model Proteasome Inhibitors in Cancer Therapy, edited by Julian in which to study ATP-dependent proteolysis.1 In a lysate Adams, which is part of the ‘Cancer Drug Discovery and from rabbit reticulocytes, where the proteolytic activity was not Development’ series from Humana Press, tells the happy tale due to lysosomes (pH optimum of 7.8), they separated two of one drug’s journey from concept, through development, fractions in a DEAE cellulose column, each one individually to FDA approval, and application. -
Characterization of the E3 Ubiquitin Ligase Pirh2
Characterization of the E3 Ubiquitin Ligase Pirh2 by Elizabeth Tai A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Medical Biophysics University of Toronto © Copyright by Elizabeth Tai (2010) Characterization of the E3 Ubiquitin Ligase Pirh2 Elizabeth Tai Doctor of Philosophy Department of Medical Biophysics University of Toronto 2010 Abstract The p53 tumour suppressor gene is inactivated by mutation in over 50% of all human cancers. The p53 protein is activated and stabilized through several post-translational modifications in response to various stresses and promotes cell cycle arrest and apoptosis. Thus, regulation of p53 is critical for normal cellular function. Pirh2 is a p53-regulated gene recently identified in our laboratory which encodes an E3 RING-finger ubiquitin ligase that binds to p53 and negatively regulates p53 by targeting it for ubiquitin- mediated proteolysis. Pirh2 is similar to another well-characterized E3 RING finger ubiquitin ligase, Mdm2, which also participates in a similar negative feedback loop with p53. At least seven E3 ubiquitin ligases are known to target p53 for degradation and the reason for this functional redundancy is unclear. The purpose of this study is to characterize Pirh2 activity. This study has two aims the first is to identify additional interacting proteins for Pirh2, and the second is to delineate Pirh2 regulation of p53. Using several tandem affinity purification strategies and a GST-pull down approach, we have identified PKC as a candidate interacting protein. II The second aim is to further characterize Pirh2 regulation of p53. Splenocytes and thymocytes from Pirh2-/- mice demonstrate a subtle increase in total p53 levels after irradiation when compared to wild-type controls. -
Steven J. Cohen, Md
STEVEN J. COHEN, MD Background Oncology Cornell University Director, Rosenfeld Cancer Center and Cancer Service Line Ithaca, NY Chief, Medical Oncology and Hematology Division (BA, Psychology, 1988-1992) Vice-Chair, Department of Medical Oncology Professor of Medical Oncology, Thomas Jefferson University, Stony Brook University School of Medicine Sidney Kimmel Cancer Center Stony Brook, NY (MD, 1992-1996) Steven J. Cohen, MD earned his Bachelor’s degree in Psychology Temple University Hospital in 1992 from Cornell Philadelphia, PA University. In 1996, he earned (Resident, Internal Medicine, 1996-1999) his medical degree from the State University of New York at Fox Chase Cancer Center Stony Brook. Dr. Cohen Temple University Hospital completed his residency in Philadelphia, PA Internal Medicine at Temple (Fellow, Medical Oncology and Hematology, 1999-2001) University Hospital in 1999. He (Chief Fellow, Medical Oncology and Hematology, 2001- completed his fellowship in 2002) Medical Oncology and (Program Director, Hematology/Oncology Fellowship, Hematology in 2002 at Fox 2009-2016) Chase Cancer Center, and also served as Chief Fellow from 2001 to 2002. Fox Chase Cancer Center Philadelphia, PA Dr. Cohen specializes in the care and treatment of GI cancers. He is a member of the American Society of Clinical (Assistant Member, Division of Medical Science, 2002- Oncology, where he has served on the Scientific Program 2004) Committee for Colorectal Cancer and chaired the Test (Attending Physician, Department of Medical Oncology, Development Committee. He is an active member of the GI 2002-2004) Committee of the Eastern Cooperative Oncology Group (Assistant Professor, Divisions of Medical and Population where he has chaired the Colorectal Cancer Subcommittee. -
Hif1α Stability in Hypoxia Is Not Oxidant-Initiated but Can Be Tuned
bioRxiv preprint doi: https://doi.org/10.1101/2020.05.05.079681; this version posted October 25, 2020. 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. Oxidants are dispensable for HIF1α stability in hypoxia Amit Kumar1, 2, 3, Manisha Vaish1, 4, Saravanan S. Karuppagounder1, 2, 3, Irina Gazaryan5, John W. Cave1, 2, 3, Anatoly A. Starkov2, 3, Elizabeth T. Anderson6, Sheng Zhang6, John T. Pinto7, Austin Rountree8, Wang Wang9, Ian R. Sweet8 and Rajiv R. Ratan1, 2, 3, * 1Burke Neurological Institute, White Plains, NY, 10605, USA 2Brain and Mind Research Institute and 3Department of Neurology, Weill Medical College of Cornell University, New York, 10016, USA 4Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, 10029, USA 5Department of Anatomy and Cell Biology, New York Medical College, Valhalla, NY, 10595, USA 6Institute for Biotechnology, Cornell University, Ithaca, NY, 14853, USA 7Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA 8Department of Medicine, University of Washington, Seattle, WA, 98108, USA 9Department of Pain and Anesthesiology, University of Washington, Seattle, WA, 98195, USA Correspondence should be addressed to: *Rajiv R. Ratan M.D., Ph.D. Burke Neurological Institute at Weill Cornell Medicine 785 Mamaroneck Avenue White Plains, NY, 10605, USA Email: [email protected] Phone: 914-597-2225 bioRxiv preprint doi: https://doi.org/10.1101/2020.05.05.079681; this version posted October 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Myc Targeted CDK18 Promotes ATR and Homologous Recombination to Mediate PARP Inhibitor Resistance in Glioblastoma
Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Ning, Jian-Fang et al. “Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma.” Nature Communications 10 (2019): 2910 © 2019 The Author(s) As Published 10.1038/S41467-019-10993-5 Publisher Springer Science and Business Media LLC Version Final published version Citable link https://hdl.handle.net/1721.1/125202 Terms of Use Creative Commons Attribution 4.0 International license Detailed Terms https://creativecommons.org/licenses/by/4.0/ ARTICLE https://doi.org/10.1038/s41467-019-10993-5 OPEN Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma Jian-Fang Ning1,2, Monica Stanciu3, Melissa R. Humphrey1, Joshua Gorham4, Hiroko Wakimoto 4, Reiko Nishihara5, Jacqueline Lees3, Lee Zou6,7, Robert L. Martuza1, Hiroaki Wakimoto 1,8 & Samuel D. Rabkin 1 1234567890():,; PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA- intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc- mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recom- bination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensi- tizing GSCs.