DOCSLIB.ORG

Heat Shock Factor 2 Protects Against Proteotoxicity by Maintaining Cell

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Heat Shock Factor 2 Protects Against Proteotoxicity by Maintaining Cell Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion Jenny Joutsen, Alejandro Jose da Silva, Jens Christian Luoto, Marek Andrzej Budzynski, Anna Serafia Nylund, Aurélie de Thonel, Jean-Paul Concordet, Valérie Mezger, Délara Sabéran-Djoneidi, Eva Henriksson, et al. To cite this version: Jenny Joutsen, Alejandro Jose da Silva, Jens Christian Luoto, Marek Andrzej Budzynski, Anna Serafia Nylund, et al.. Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion. Cell Reports, Elsevier Inc, 2020, 30 (2), pp.583-597.e6. 10.1016/j.celrep.2019.12.037. hal-02929926 HAL Id: hal-02929926 https://hal.archives-ouvertes.fr/hal-02929926 Submitted on 6 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Article Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion Graphical Abstract Authors Jenny Joutsen, Alejandro Jose Da Silva, Jens Christian Luoto, ..., De´ lara Sabe´ ran-Djoneidi, Eva Henriksson, Lea Sistonen Correspondence lea.sistonen@abo.fi In Brief Joutsen et al. show that heat shock factor 2 (HSF2) is essential for cell survival during prolonged proteotoxicity. Lack of HSF2 leads to marked misregulation of cadherin superfamily genes and functional impairment of cell-cell adhesion. Cell-cell adhesion is found to be a key determinant of proteotoxic stress resistance. Highlights d HSF2 is required to maintain cell-cell adhesion d HSF2 deficiency leads to downregulation of cadherin superfamily genes d Impaired cell-cell adhesion sensitizes cells to prolonged proteotoxic stress d Cadherin-mediated cell-cell adhesion is a survival determinant upon proteotoxicity Joutsen et al., 2020, Cell Reports 30, 583–597 January 14, 2020 ª 2019 The Author(s). https://doi.org/10.1016/j.celrep.2019.12.037 Cell Reports Article Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion Jenny Joutsen,1,2,7 Alejandro Jose Da Silva,1,2,7 Jens Christian Luoto,1,2 Marek Andrzej Budzynski,1,2 Anna Serafia Nylund,1,2 Aurelie de Thonel,3,4,5 Jean-Paul Concordet,6 Vale´ rie Mezger,3,4,5 De´ lara Sabe´ ran-Djoneidi,3,4,5 Eva Henriksson,1,2 and Lea Sistonen1,2,8,* 1Faculty of Science and Engineering, Cell Biology, A˚ bo Akademi University, Tykisto¨ katu 6, 20520 Turku, Finland 2Turku Bioscience Centre, University of Turku and A˚ bo Akademi University, Tykisto¨ katu 6, 20520 Turku, Finland 3CNRS, UMR 7216 ‘‘Epigenetic and Cell Fate,’’ 75250 Paris Cedex 13, France 4University of Paris Diderot, Sorbonne Paris Cite´ , 75250 Paris Cedex 13, France 5De´ partement Hospitalo-Universitaire DHU PROTECT, Paris, France 6INSERM U1154, CNRS UMR 7196, Muse´ um National d’Histoire Naturelle, Paris, France 7These authors contributed equally 8Lead Contact *Correspondence: lea.sistonen@abo.fi https://doi.org/10.1016/j.celrep.2019.12.037 SUMMARY mediated by heat shock transcription factors (HSFs; Joutsen and Sistonen, 2019). Upon activation, HSFs oligomerize, accu- Maintenance of protein homeostasis, through induc- mulate in the nucleus, and bind to their target heat shock ele- ible expression of molecular chaperones, is essential ments (HSEs) at multiple genomic loci (Vihervaara et al., 2013, for cell survival under protein-damaging conditions. 2017; Mahat et al., 2016). The canonical HSF target genes The expression and DNA-binding activity of heat encode molecular chaperones, such as heat shock proteins shock factor 2 (HSF2), a member of the heat shock (HSPs), which assist in the maintenance of a correct protein transcription factor family, increase upon exposure folding environment by refolding the misfolded proteins or di- recting them to protein degradation machineries (Hartl et al., to prolonged proteotoxicity. Nevertheless, the spe- 2011). In addition, HSFs are important in a variety of other phys- cific roles of HSF2 and the global HSF2-dependent iological and pathological processes and the repertoire of HSF gene expression profile during sustained stress target genes has been shown to extend beyond the HSPs have remained unknown. Here, we found that HSF2 (Hahn et al., 2004; A˚ kerfelt et al., 2010; Gonsalves et al., 2011; is critical for cell survival during prolonged proteo- Mendillo et al., 2012; Riva et al., 2012; Bjo¨ rk et al., 2016; Li toxicity. Strikingly, our RNA sequencing (RNA-seq) et al., 2016). analyses revealed that impaired viability of HSF2- The human genome encodes six HSF family members (HSF1, deficient cells is not caused by inadequate induction HSF2, HSF4, HSF5, HSFX, and HSFY), of which HSF1 and HSF2 of molecular chaperones but is due to marked down- are the most extensively studied (Joutsen and Sistonen, 2019). regulation of cadherin superfamily genes. We Although these factors are homologous in their DNA-binding do- demonstrate that HSF2-dependent maintenance of mains, they share only a few similarities in the tissue expression patterns, regulatory mechanisms, and signals that stimulate their cadherin-mediated cell-cell adhesion is required for activity (Jaeger et al., 2016; Gomez-Pastor et al., 2018). HSF1 is protection against stress induced by proteasome in- essential for HSP expression and cell survival under acute stress hibition. This study identifies HSF2 as a key regulator conditions (Joutsen and Sistonen, 2019). HSF2 is an unstable of cadherin superfamily genes and defines cell-cell protein and its expression is highly context dependent, fluctu- adhesion as a determinant of proteotoxic stress ating in different cell and tissue types (Sarge et al., 1991; Alastalo resistance. et al., 1998), developmental stages (Mezger et al., 1994; Rallu et al., 1997), and during the cell cycle (Elsing et al., 2014). Conse- INTRODUCTION quently, regulation of HSF2 protein levels has been considered to be the main determinant of its DNA-binding capacity (Mathew The cells in a human body are constantly exposed to environ- et al., 1998; Budzynski and Sistonen, 2017). Interestingly, the mental stressors, which challenge the maintenance of protein DNA-binding activity of HSF2 increases in cells exposed to lac- homeostasis, also called proteostasis. To survive insults that tacystin- or MG132-induced proteasome inhibition (Kawazoe disturb proteostasis, cells rely on a selection of protective mech- et al., 1998; Mathew et al., 1998; Pirkkala et al., 2000), indicating anisms that can be launched upon stress exposures. The heat that HSF2 can respond to proteostasis disruption. Nevertheless, shock response is a well-conserved stress protective pathway the molecular details of the activation mechanisms of HSF2 are that is induced in response to cytosolic protein damage and currently not conclusively understood. Cell Reports 30, 583–597, January 14, 2020 ª 2019 The Author(s). 583 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Figure 1. HSF2 Is Upregulated upon Prolonged Bortezomib (BTZ) Treatment (A) Immunoblot analysis of HSF2 expression. U2OS WT cells were treated with indicated concentrations of BTZ for 6 or 22 h. Control (C) cells were treated with DMSO. Tubulin was used as a loading control. (B) Confocal microscopy images of HSF2 immunofluorescence staining. U2OS WT cells were plated on coverslips and treated with 25 nM BTZ for 6, 10, or 22 h. Control cells were treated with DMSO. Samples were fixed and stained with anti-HSF2 antibody. DAPI was used for DNA detection. The overlay of HSF2 and DAPI maximum intensity projection signals is shown in merge. Scale bar, 100 mm. (C) Immunoblot analysis of HSF2 in subcellular fractions. U2OS WT cells were treated with 25 nM BTZ for 6 and 22 h. Control cells were treated with DMSO. Wc, whole cell fraction; Cy, cytoplasmic fraction; and Nu, nuclear fraction. Lamin A/C and Tubulin were used as fractionation controls. The ubiquitin-proteasome system is one of the main cellular In this study, we show that HSF2 is critical for survival of cells mechanisms regulating protein turnover, thereby affecting multi- during prolonged proteasome inhibition. To our surprise, the ple aspects of cell physiology, such as signal transduction and genome-wide expression analyses revealed that HSF2 disrup- apoptosis (Hershko and Ciechanover, 1998; Varshavsky, 2012). tion results in a profound downregulation of genes belonging Due to the fundamental function in cell physiology, the protea- to the cadherin superfamily and subsequent functional impair- some complex has emerged as an important target for anti-can- ment of cell-cell adhesion. Furthermore, we show that failure to cer therapy (Deshaies, 2014). The most common drug to inhibit form adequate cadherin-mediated cell-cell adhesion contacts proteasome function is bortezomib (BTZ; PS-341, VELCADE), predisposes cells to proteasome inhibition-induced cell death. which is currently used as a standard treatment in hematological These results identify HSF2 as a key regulator of cadherin genes. malignancies (Chen et al., 2011). BTZ is a dipeptide boronic acid Taken together, we show that by maintaining cadherin-mediated derivative that
Load more

Recommended publications
  • A Clinicopathological and Molecular Genetic Analysis of Low-Grade Glioma in Adults
    A CLINICOPATHOLOGICAL AND MOLECULAR GENETIC ANALYSIS OF LOW-GRADE GLIOMA IN ADULTS Presented by ANUSHREE SINGH MSc A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy Brain Tumour Research Centre Research Institute in Healthcare Sciences Faculty of Science and Engineering University of Wolverhampton November 2014 i DECLARATION This work or any part thereof has not previously been presented in any form to the University or to any other body whether for the purposes of assessment, publication or for any other purpose (unless otherwise indicated). Save for any express acknowledgments, references and/or bibliographies cited in the work, I confirm that the intellectual content of the work is the result of my own efforts and of no other person. The right of Anushree Singh to be identified as author of this work is asserted in accordance with ss.77 and 78 of the Copyright, Designs and Patents Act 1988. At this date copyright is owned by the author. Signature: Anushree Date: 30th November 2014 ii ABSTRACT The aim of the study was to identify molecular markers that can determine progression of low grade glioma. This was done using various approaches such as IDH1 and IDH2 mutation analysis, MGMT methylation analysis, copy number analysis using array comparative genomic hybridisation and identification of differentially expressed miRNAs using miRNA microarray analysis. IDH1 mutation was present at a frequency of 71% in low grade glioma and was identified as an independent marker for improved OS in a multivariate analysis, which confirms the previous findings in low grade glioma studies.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells
    TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells Wei Xiong,1 Nicolas Grillet,1 Heather M. Elledge,1 Thomas F.J. Wagner,1 Bo Zhao,1 Kenneth R. Johnson,2 Piotr Kazmierczak,1 and Ulrich Mu¨ller1,* 1The Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA 2The Jackson Laboratory, Bar Harbor, ME 04609, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2012.10.041 SUMMARY deflection of the stereociliary bundles, which directly control the activity of the mechanotransduction channels in stereocilia. Hair cells are mechanosensors for the perception of It is thought that tip links, fine extracellular filaments that connect sound, acceleration, and fluid motion. Mechano- the tips of neighboring stereocilia, transmit tension force onto transduction channels in hair cells are gated by tip the transduction channels (Gillespie and Mu¨ ller, 2009). links, which connect the stereocilia of a hair cell in In recent years, significant progress has been made in the direction of their mechanical sensitivity. The the identification of components of the mechanotransduction molecular constituents of the mechanotransduction machinery of hair cells (Figure 1A). These studies have shown that tip links are formed by CDH23 homodimers that interact channels of hair cells are not known. Here, we show with PCDH15 homodimers to form the upper and lower parts that mechanotransduction is impaired in mice lack- of tip links (Ahmed et al., 2006; Kazmierczak et al., 2007; ing the tetraspan TMHS. TMHS binds to the tip-link Siemens et al., 2004; So¨ llner et al., 2004).
    [Show full text]
  • 1 Structural Studies of a Protocadherin-15 Fragment Essential for Hearing
    Structural Studies of a Protocadherin-15 Fragment Essential for Hearing A thesis presented By Conghui Chen To The Committee on Degrees in Chemistry ad Biochemistry In partial fulfillment of the requirements For a degree of Bachelor of Science with Research Distinction In the field of Biochemistry Research Advisor: Dr. Marcos Sotomayor, Assistant Professor of Department of Chemistry and Biochemistry Defense Committee: Dr. John Shimko, Chemistry Lecturer of Department of Chemistry and Biochemistry The Ohio State University Columbus, Ohio April 13th, 2016 1 Statement of Research I conducted the research presented in this thesis under the professional guidance of Dr. Marcos Sotomayor of The Ohio State University Main Campus Chemistry and Biochemistry Department. I joined the Sotomayor lab in August of 2013, during my second year at the university. I was trained in the process of protein purification and cell culture by visiting graduate student Deryanur Kilic in conjunction with Dr. Sotomayor. Dr. Sotomayor offered knowledgeable tutelage in designing and performing the experiments, analyzing data, and the writing of this thesis. All molecular modeling and analysis was performed with the guidance and assistance from Dr. Marcos Sotomayor and Dr. Raul Araya-Secchi. My research was generously funded by The Ohio State University Chemistry and Biochemistry Undergraduate Research Scholarship from autumn 2013 until spring 2015. I performed research as part of the Biochemistry 4998 and 4999 courses as a requirement for the completion of the thesis. 2 Abstract Sound travels through the external and middle ear to the fluid-filled cochlea where mechanosensitive hair cells transform it into electrochemical signals. On the apical side of each hair cell, a set of hair-like protrusions, called stereocilia form a bundle with filamentous connections (tip links) that are essential for hearing.
    [Show full text]
  • Tip-Link Protein Protocadherin 15 Interacts with Transmembrane Channel-Like Proteins TMC1 and TMC2
    Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2 Reo Maedaa,b,1, Katie S. Kindta,b,1,2, Weike Moa,b,1, Clive P. Morgana,b, Timothy Ericksona,b, Hongyu Zhaoa,b, Rachel Clemens-Grishama,b, Peter G. Barr-Gillespiea,b, and Teresa Nicolsona,b,3 aOregon Hearing Research Center and bVollum Institute, Oregon Health and Science University, Portland, OR 97239 Edited by A. J. Hudspeth, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, and approved July 23, 2014 (received for review February 3, 2014) The tip link protein protocadherin 15 (PCDH15) is a central compo- vestibular deficits, along with the complete absence of normal nent of the mechanotransduction complex in auditory and vestib- mechanotransduction currents in auditory and vestibular hair cells ular hair cells. PCDH15 is hypothesized to relay external forces to the (17). Changes in calcium permeability through the transduction mechanically gated channel located near its cytoplasmic C terminus. channel of cochlear hair cells were observed for Tmc1 Tmc2 How PCDH15 is coupled to the transduction machinery is not clear. double-mutant mice, as well as in single mutants of either gene Using a membrane-based two-hybrid screen to identify proteins (10, 18, 19). In further support of the idea that TMCs are pore- that bind to PCDH15, we detected an interaction between zebrafish forming subunits of the transduction channel, mouse vestibular Pcdh15a and an N-terminal fragment of transmembrane channel- hair cells that express only the dominant Beethoven (M412K) al- like 2a (Tmc2a). Tmc2a is an ortholog of mammalian TMC2, which lele of Tmc1, in the absence of any wild-type TMC1 or TMC2, along with TMC1 has been implicated in mechanotransduction in display altered single-channel transduction currents (10).
    [Show full text]
  • Cadherins As Targets for Genetic Diseases
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Cadherins as Targets for Genetic Diseases Aziz El-Amraoui1,2,3 and Christine Petit1,2,3,4 1Institut Pasteur, Unite´ de Ge´ne´tique et Physiologie de l’Audition, 25 rue du Dr Roux, 75015 Paris, France 2INSERM UMRS587, 75015 Paris, France 3UPMC, F75015 Paris, France 4Colle`ge de France, 75005 Paris, France Correspondence: [email protected], [email protected] The 6-billion human population provides a vast reservoir of mutations, which, in addition to the opportunity of detecting very subtle defects, including specific cognitive dysfunctions as well as late appearing disorders, offers a unique background in which to investigate the roles of cell–cell adhesion proteins. Here we focus on inherited human disorders involving members of the cadherin superfamily. Most of the advances concern monogenic disorders. Yet,with the development of single nucleotide polymorphism (SNP) association studies, cad- herin genes are emerging as susceptibility genes in multifactorial disorders. Various skin and heart disorders revealed the critical role played by desmosomal cadherins in epidermis, hairs, and myocardium, which experience high mechanical stress. Of particular interest in that respect is the study of Usher syndrome type 1 (USH1), a hereditary syndromic form of deafness. Studies of USH1 brought to light the crucial role of transient fibrous links formed by cadherin 23 and protocadherin 15 in the cohesion of the developing hair bundle, the mechanoreceptive structure of the auditory sensory cells, as well as the involvement of these cadherins in the formation of the tip-link, a key component of the mechano-electrical transduction machinery.
    [Show full text]
  • Identification and the Significance of Selective Proteins in Bile And
    University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 12-2014 Identification and the Significance of Selective Proteins in Bile and Plasma of Normal and Health- compromised Chickens Balamurugan Packialakshmi University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Analytical Chemistry Commons, Animal Diseases Commons, and the Poultry or Avian Science Commons Recommended Citation Packialakshmi, Balamurugan, "Identification and the Significance of Selective Proteins in Bile and Plasma of Normal and Health- compromised Chickens" (2014). Theses and Dissertations. 2083. http://scholarworks.uark.edu/etd/2083 This Dissertation is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. Identification and the Significance of Selective Proteins in Bile and Plasma of Normal and Health-compromised Chickens Identification and the Significance of Selective Proteins in Bile and Plasma of Normal and Health-compromised Chickens A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell and Molecular Biology by Balamurugan Packialakshmi Tamilnadu Agricultural University, Bachelor of Technology in Agricultural Biotechnology, 2007 Govind Ballabh Pant University of Agriculture and Technology, Master of Science in Molecular Biology and Biotechnology, 2009 December 2014 University of Arkansas This dissertation is approved for the recommendation to the graduate council. _____________________ Dr. Narayan. C. Rath Dissertation Director _____________________ _____________________ Dr. Jackson O. Lay, Jr. Dr. Robert F. Wideman, Jr. Committee member Committee member ____________________ Dr.
    [Show full text]
  • Integrin Α8 and Pcdh15 Act As a Complex to Regulate Cilia Biogenesis in Sensory Cells Linda Goodman and Marisa Zallocchi*
    © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 3698-3712 doi:10.1242/jcs.206201 RESEARCH ARTICLE Integrin α8 and Pcdh15 act as a complex to regulate cilia biogenesis in sensory cells Linda Goodman and Marisa Zallocchi* ABSTRACT sensory neuron physiology (hearing/balance, olfaction and vision), The way an organism perceives its surroundings depends on sensory as well as organ development and function (Delmaghani et al., systems and the highly specialized cilia present in the neurosensory 2016; Grati et al., 2015; Jagger et al., 2011; Rachel et al., 2012). cells. Here, we describe the existence of an integrin α8 (Itga8) and Hair cells, the neurosensory cells of the auditory and vestibular protocadherin-15a (Pcdh15a) ciliary complex in neuromast hair cells systems, are the mechanosensors for the perception of sound and in a zebrafish model. Depletion of the complex via downregulation or head movements. Projecting from their apical surface is the hair loss-of-function mutation leads to a dysregulation of cilia biogenesis bundle, which consists of rows of ascending height actin-filled and endocytosis. At the molecular level, removal of the complex stereocilia tethered to a single primary cilium, the kinocilium blocks the access of Rab8a into the cilia as well as normal recruitment (Cosgrove and Zallocchi, 2014). During hair bundle development of ciliary cargo by centriolar satellites. These defects can be reversed the kinocilium is physically connected via extracellular linkages by the introduction of a constitutively active form of Rhoa, suggesting formed between cadherin-23 (Cdh23) and protocadherin-15 that Itga8–Pcdh15a complex mediates its effect through the (Pcdh15), which are essential for proper hair bundle integrity and activation of this small GTPase and probably by the regulation of function (Kazmierczak et al., 2007; Webb et al., 2011).
    [Show full text]
  • The NIH Catalyst Spoke with Copeland Chief Se- and Jenkins— and CONTENTS Nior Investigator, Respectively, of the Bill Branson
    Fostering Communication and Collaboration The nihCatalyst A Publication for NIH Intramural Scientists National Institutes of Health bOffice of the Director' e Volume 11, Issue 6* November-December 2003 CC Celebrates 50th at Research Festival > the Sum of the Parts Giants Standing Copeland and Jenkins On the Shoulders of Giants And the Development Of Mouse Cancer Genetics by Fran Pollner DeVita it by PeterJ. Kozel ince put this way: “It’s nice V to come home.” And in one way or an- other, each of the speak- ers who took the stage to commemorate the CC’s 50th anniversary ex- pressed an affection for the daily working envi- ronment at NIFI and its research hospital that Bill Branson conjured up the image of CC DirectorJohn Gallin salutes former and current NIH NancyJenkins Neal Copeland home: scientists and a half-century of transforming research t’s hard to say what the NIH sci- The collaborative entific directors were honoring and feisty spirit among colleagues remi- The perseverance, warmth, and mu- I when they picked husband-and- niscent of the best kind of sibling cama- tual regard that characterized the rela- wife cancer genetics investigators raderie—and squabbling tionships between the physician-re- Neal Copeland and Nancy Jenkins searchers and the patients undergoing to present this year’s Mider Lecture. experimental treatments, sometimes ex- Was it their legacy—almost 700 pa- tending through decades of follow-up pers and the reference mouse ge- The culture of NIFf, like that in a nome map? Was it their astonishing nurturing family, that supported the pur- record of training successful scien- suit of new ideas and personal intellec- tists? Was it their innovative “recom- tual expansion bineering” technique that’s revolu- They all saw the past—studded with tionizing the manipulation of DNA? the gems of biomedical research that Or was it their almost unparalleled, contributed enormously to science and highly productive collaboration, now human health—as prologue to the fu- in its third decade? ture.
    [Show full text]
  • The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease
    International Journal of Molecular Sciences Review The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease Izarbe Aísa-Marín 1,2 , Rocío García-Arroyo 1,3 , Serena Mirra 1,2 and Gemma Marfany 1,2,3,* 1 Departament of Genetics, Microbiology and Statistics, Avda. Diagonal 643, Universitat de Barcelona, 08028 Barcelona, Spain; [email protected] (I.A.-M.); [email protected] (R.G.-A.); [email protected] (S.M.) 2 Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Universitat de Barcelona, 08028 Barcelona, Spain 3 Institute of Biomedicine (IBUB, IBUB-IRSJD), Universitat de Barcelona, 08028 Barcelona, Spain * Correspondence: [email protected] Abstract: Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely complex splicing programs and display the highest number of alternative splicing events. As an extension of the central nervous system, the retina constitutes an excellent system to illustrate the high diversity of neural transcripts. The retina expresses retinal specific splicing factors and produces a large number of alternative transcripts, including exclusive tissue-specific exons, which require an exquisite regulation. In fact, a current challenge in the genetic diagnosis of inherited retinal diseases stems from the lack of information regarding alternative splicing of retinal genes, as a considerable percentage of mutations alter splicing Citation: Aísa-Marín, I.; or the relative production of alternative transcripts. Modulation of alternative splicing in the retina García-Arroyo, R.; Mirra, S.; Marfany, is also instrumental in the design of novel therapeutic approaches for retinal dystrophies, since it G.
    [Show full text]
  • Dynamic Changes of Muscle Insulin Sensitivity After Metabolic Surgery
    ARTICLE https://doi.org/10.1038/s41467-019-12081-0 OPEN Dynamic changes of muscle insulin sensitivity after metabolic surgery Sofiya Gancheva1,2,3,11, Meriem Ouni 3,4,11, Tomas Jelenik2,3, Chrysi Koliaki1,2,3,5, Julia Szendroedi1,2,3, Frederico G.S. Toledo6, Daniel F. Markgraf 2,3, Dominik H. Pesta 2,3, Lucia Mastrototaro2,3, Elisabetta De Filippo2,3, Christian Herder 1,2,3, Markus Jähnert 3,4, Jürgen Weiss3,7, Klaus Strassburger 3,8, Matthias Schlensak9, Annette Schürmann 3,4,10,12 & Michael Roden 1,2,3,12 1234567890():,; The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocel- lular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accom- panies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity. 1 Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. 2 Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany. 3 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
    [Show full text]
  • Species-Dependent Heterophilic and Homophilic Cadherin Interactions In
    bioRxiv preprint doi: https://doi.org/10.1101/2020.09.01.278846; this version posted September 2, 2020. 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-NC-ND 4.0 International license. 1 SPECIES-DEPENDENT HETEROPHILIC AND HOMOPHILIC CADHERIN INTERACTIONS IN 2 INTESTINAL INTERMICROVILLAR LINKS 3 4 Michelle E. Gray*1, Zachary R. Johnson*§2, Debadrita Modak*2, Matthew J. Tyska3, and Marcos Sotomayor#1,2 5 1Ohio State Biochemistry Program 6 2Department of Chemistry and Biochemistry 7 The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210 8 3Department of Cell and Developmental Biology 9 Vanderbilt University School of Medicine, Nashville, TN 37232 10 *Co-first authors 11 §Current address: Marshall University, Joan C. Edwards School of Medicine, Huntington, WV 25701 12 # Corresponding Author 13 E-mail: [email protected] 14 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.01.278846; this version posted September 2, 2020. 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-NC-ND 4.0 International license. 1 ABSTRACT 2 Enterocytes are specialized epithelial cells lining the luminal surface of the small intestine that build densely packed 3 arrays of microvilli known as brush borders. These microvilli drive nutrient absorption and are arranged in a hexagonal 4 pattern maintained by intermicrovillar links formed by two non-classical members of the cadherin superfamily of calcium- 5 dependent cell adhesion proteins: protocadherin-24 (PCDH24, also known as CDHR2) and the mucin-like protocadherin 6 (CDHR5).
    [Show full text]