DOCSLIB.ORG

PDF Hosted at the Radboud Repository of the Radboud University Nijmegen

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/85871 Please be advised that this information was generated on 2021-09-29 and may be subject to change. ISOFORMS IN MUSCLE AND BRAIN CELLS localization and function • ralph j.a. oude ophuis • 2011 9 789088 912344 > ISBN 978-90-8891234,-4 DMPK ISOFORMS IN MUSCLE AND BRAIN CELLS LOCALIZATION AND FUNCTION Voor het bijwonen van de openbare verdediging van het proefschrift van RALPH J.A. OUDE OPHUIS DMPK ISOFORMS IN MUSCLE AND BRAIN CELLS LOCALIZATION AND FUNCTION op vrijdag 1 april 2011 om 13:00u precies in de Aula van de Radboud Universiteit Nijmegen aan de Comeniuslaan 2 te Nijmegen Na afloop van de verdediging is er een receptie ter plaatse PARANIMFEN Susan Mulders [email protected] Rinske van de Vorstenbosch r.vandevorstenbosch(§) ncmls.ru.nl DMPK ISOFORMS IN MUSCLE AND BRAIN CELLS LOCALIZATION AND FUNCTION ISBN-13 978-90-8891234-4 ISBN-10 90-8891-234-3 Printed by Proefsohriftmaken.nl || Printyourthesis.com Published by Uitgeverij BOXPress, Oisterwijk DMPK ISOFORMS IN MUSCLE AND BRAIN CELLS LOCALIZATION AND FUNCTION Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het college van decanen in het openbaar te verdedigen op vrijdag 1 april 2011 om 13:00 uur precies door Raphaël Johannes Antonius Oude Ophuis geboren op 24 oktober 1978 te Sint-Oedenrode Promotor Prof. dr. B. Wieringa Copromotores Dr. D.G. Wansink Dr. J.A.M. Fransen Manuscriptcommissie Prof. dr. H.G. Brunner Prof. dr. J.A.M. Smeitink Dr. F.J.M. van Kuppeveld The studies presented in this thesis were performed at the Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands. Financial support was obtained from the Prinses Beatrix Fonds, the Stichting Spieren voor Spieren, the Muscular Dystrophy Association (MDA) and the Association Française contre les Myopathies (AFM). TABLE OF CONTENTS Chapter 1 9 General introduction • 1 Myotonic Dystophy type 1 11 • 2 DM1 molecular pathogenesis 12 • 3 DMPK protein 16 • 4 DMPK splice isoforms 18 • 5 Tail-anchored proteins 22 • 6 DMPK substrates and function 25 • 7 Aim and outline of this thesis 28 Chapter 2 31 DMPK protein isoforms are differentially expressed in myogenic and neu­ ral cell lineages Chapter 3 49 Topology and specificity of membrane insertion of tail-anchored DMPK isoforms Chapter 4 77 A tail-anchored myotonic dystrophy protein kinase isoform induces peri­ nuclear clustering of mitochondria, autophagy and apoptosis Chapter 5 97 Myotonic dystrophy protein kinase isoforms A and C exert differential control over Ca2+ mobilization in myotubes Chapter 6 121 Summarizing Discussion References 132 Nederlandse samenvatting 146 Abbreviations 150 Dankwoord 152 Curriculum vitae 156 Publications 157 i CHAPTER 1 GENERAL INTRODUCTION GENERAL INTRODUCTION Í • 1. Myotonic Dystophy type 1 (DM1) DM is the most common genetic determined muscular dystrophy in adults at a prevalence of 1:8000 (101) and was first described by Steinert (266), and Batten and Gibb (10) about one century ago. We now know that this multisystemic neuromuscular disorder can be divided into two subtypes with different prevalence: DM type 1 (DM1, also known as Steinert dis­ ease; MIM 160900) and DM type 2 (DM2, also known as proxim al myo­ tonic myopathy, MIM 602668). DM symptoms vary in severity and mostly manifest themselves as muscle related. Prominent symptoms include myotonia, distal and proxim al muscle weakness and atrophy, gastroin­ testinal transit problems, and cardiac aberrations like conduction de­ fects and arrhythmias. Cardiac problems are generally considered the leading cause of death in DM. Furthermore, the central nervous system can be affected, and cataract and endocrine problems can be involved, illus trating the multisystemic character of the disease (summarized in Fig. 1A). This plethora of symptoms together with long asymptomatic Figure 1 • DM1 molecular A Muscular pathogenesis: symptoms and myotonia +++ locus. distal muscle weakness +++ (A) Characteristic symptoms proximal muscle weakness ++ of DM1. The frequency of muscle atrophy ++ facial muscles ++ symptoms is indicated by a hip girdle muscles + scale from + to +++. Typical finger flexors +++ skeletal muscle features are neck muscles +++ illu s tra te d in the draw ing foot dorsiflexors ++ quadriceps +++ darkest shading indicates cardiac arrythmia ++ most severely affected skel­ gastrointestinal problems + etal m uscle areas. (B) DM1 uterus + locus organization. The (CTG)n repeat tra ct is Non-muscular cataract ++ located in a gene-dense re ­ hypogonadism ++ gion on human chromosome insulin insensitivity + 19q13 in exon 15 of the hypersomnia ++ DMPK gene, which overlaps mental retardation + with the promoter region of congenital DM + the SIX5 gene. Rectangles indicate exons (grey, DMWD; + present; ++ frequent; +++ usual black, DMPK; white, SIX5). The straight line represents B locus (19q13) N orm al 5 < (CTG)n < 35 introns and intergenic se­ DM1 quences. Arrows denote start P re m u ta tio n 35 < (CTG)n < 49 l L (CTG)n ^ and direction of transcription. M ild 50 < (CTG)n < 150 Disease classification anc C la ssic 100 < (CTG)n < 1000 corresponding number of -faotifr] i in //—tf-E—i-o o (CTG)n repeats is indicated DMWD DMPK SIX5 C o n g e n ita l (CTG)n > 1000 to the right. 1 • General Introduction periods and a variable age of onset make DM a difficult to diagnose dis­ order (94). Contrary to DM2, DM1 can also occur as a severe congenital form characterized by high neonatal mortality, hypotonia, mental retar­ dation and respiratory distress (101). In the early nineties of the twentieth century the mutation underly­ ing DM1 was discovered by several groups on chromosome 19q13 in the 3'-UTR of the DMPK gene (Fig. 1B) (26, 86, 175). Several years later, a (CCTG)n mutation in intron 1 of the zinc finger protein 9 (ZNF9) mapping to chromosome 3q21 was identified as the cause of DM2 (167, 225). For DM1, it has been found that severity of symptoms and length of the repeat are correlated (Fig. 1B). An unaffected person carries a short repeat composed of 5-35 CTG triplets, while mildly affected patients carry 35-150 CTG units in their affected allele. Patients with the classical DM1 phenotype have repeats of 100-1000 CTGs and the most severely affected individuals carry a repeat of over 1000 CTGs (101, 116). Once the (CTG)n repeat crosses a threshold of 35 CTG triplets, it becomes un­ stable, resulting in expansion in somatic tissues (187) and in successive generations. Repeat expansion causes anticipation, meaning that severity of disease increases between generations and symptoms appear earlier in life (31, 102, 187). In order to better understand the multisystemic character of DM1 it is of paramount importance to gain extensive knowledge about DMPK mRNA and protein functions and expression patterns. • 2. DM1 molecular pathogenesis DM1 is now classified as an unstable mini- or m icrosatellite or DNA expansion disorder, a heterogeneous family of disorders to which also Huntington's disease, FRAXA, various types of spinocerebellar ataxia (94) and several other neurodegenerative disorders belong. Upon discovery that the mutation leading to DM1 is localized in the 3'-UTR of the DMPK gene, it was realized that special mechanisms of pathogenesis must be operational because formation of abnormal protein structure cannot be involved. Hence, several hypotheses were postulated to explain the mul- tisystemic nature of DM1 pathology. • 2.1. RNA pathogenesis The most prevalent and best supported explanation for the molecular pathology of DM1 is an RNA-based toxic gain-of-function mechanism, in which newly formed transcription products containing large (CUG)n repeats are trapped in the nucleus, where they aggregate with nuclear proteins to form ribonuclear protein complexes of abnormal nature (75, 111, 129, 181). The end result is global m isregulation of gene expres­ sion (43, 65, 225). Just lately, it was speculated that soluble transcripts containing long CUG-repats are also able to bind transcription and splice factors, in this way contributing to gene misregulation (132). Length of the repeat is correlated with binding of nuclear proteins, nuclear reten­ tion and formation of nuclear aggregates (54, 58). Analysis of ribonuclear foci in muscle and brain tissue from DM1 patients revealed presence of splice factors of the muscleblind family (MBNL 1, 2 and 3) within the 1 1 • General Introduction 12 ribonucleoprotein (RNP) aggregates. It is therefore commonly believed that the amount of MBNL available for proper regulation of splicing is reduced. Although not found in nuclear foci but believed to bind soluble, expanded transcripts, other RNA processing factors able to bind (CUG) n repeats are upregulated or are behaving abnormally, like CUG-binding protein 1 (CUG-BP1) a member of the CUG-BP and ETR3-like (CELF) fam ilies of factors (132, 278) or HnRNP-H (139). Furthermore, several other proteins not involved in splicing such as protein kinase R (276), transcription factor SP1 (specific protein 1), signal transducers and ac­ tivators of transcription (STAT1 and 3), the retinoic acid receptor gamma subunit (58, 65) and Nkx2.5 (306) may also be involved in DM1 via an RNA-mediated mechanism. In DM1 tissues, multiple splice abnormalities have been described (58), including in muscle: splicing of the mRNAs for chloride channel 1 (ClC-1 ) (40, 180), sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (143), cardiac troponin T (110, 219), insulin receptor (IR) (248), and the ryanodine receptor (143). In brain, processing of the mRNAs for Tau (164, 253), and amyloid precursor protein (129) is misregulated.
Recommended publications
  • Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

    Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

    G C A T T A C G G C A T genes Review Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling Aoife A. Nolan 1, Nourhan K. Aboud 1, Walter Kolch 1,2,* and David Matallanas 1,* 1 Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; [email protected] (A.A.N.); [email protected] (N.K.A.) 2 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland * Correspondence: [email protected] (W.K.); [email protected] (D.M.) Abstract: Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharma- cological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration. Keywords: RAF kinase-independent; RAS; MST2; ASK; PLK; RHO-α; apoptosis; cell cycle; cancer therapy Citation: Nolan, A.A.; Aboud, N.K.; Kolch, W.; Matallanas, D. Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling.
  • Establishment and Genomic Characterization of a Sporadic Malignant Peripheral Nerve Sheath Tumor Cell Line Jody Fromm Longo1, Stephanie N

    Establishment and Genomic Characterization of a Sporadic Malignant Peripheral Nerve Sheath Tumor Cell Line Jody Fromm Longo1, Stephanie N

    www.nature.com/scientificreports OPEN Establishment and genomic characterization of a sporadic malignant peripheral nerve sheath tumor cell line Jody Fromm Longo1, Stephanie N. Brosius3,5,7, Iya Znoyko1, Victoria A. Alers1, Dorea P. Jenkins1, Robert C. Wilson1,2, Andrew J. Carroll4, Daynna J. Wolf1, Kevin A. Roth6 & Steven L. Carroll1,2,3* Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived neoplasms that occur sporadically or in patients with neurofbromatosis type 1 (NF1). Preclinical research on sporadic MPNSTs has been limited as few cell lines exist. We generated and characterized a new sporadic MPNST cell line, 2XSB, which shares the molecular and genomic features of the parent tumor. These cells have a highly complex karyotype with extensive chromothripsis. 2XSB cells show robust invasive 3-dimensional and clonogenic culture capability and form solid tumors when xenografted into immunodefcient mice. High-density single nucleotide polymorphism array and whole exome sequencing analyses indicate that, unlike NF1-associated MPNSTs, 2XSB cells have intact, functional NF1 alleles with no evidence of mutations in genes encoding components of Polycomb Repressor Complex 2. However, mutations in other genes implicated in MPNST pathogenesis were identifed in 2XSB cells including homozygous deletion of CDKN2A and mutations in TP53 and PTEN. We also identifed mutations in genes not previously associated with MPNSTs but associated with the pathogenesis of other human cancers. These include DNMT1, NUMA1, NTRK1, PDE11A, CSMD3, LRP5 and ACTL9. This sporadic MPNST-derived cell line provides a useful tool for investigating the biology and potential treatment regimens for sporadic MPNSTs. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms derived from the Schwann cell lineage1,2.
  • Signaling in the Type I Interferon Antiviral Innate Immune Response

    Signaling in the Type I Interferon Antiviral Innate Immune Response

    Signaling in the type I interferon antiviral innate Most vertebrate cells respond to viral infection by producing and sensing NF-κB, transcription factors that trigger the expression of genes encod- immune response type I interferon (IFN), which establishes an antiviral state characterized ing type I IFN proteins and other mediators of innate immune activation. by inhibition of viral replication, apoptosis of infected cells, and stimu- Type I IFN proteins bind to the type I IFN receptor and activate Janus ki- David E Levy & Isabelle J Marié lation of innate immune mechanisms that augment subsequent adaptive nase–signal transducer and activator of transcription (Jak-STAT) signaling 4,2 immune responses. Vertebrate cells detect virus infection either via the and formation of the trimeric transcription factor complex ISGF3, which #$ cytoplasmic RNA helicase sensors RIG-I and MDA-5, the cytoplasmic promotes expression of antiviral effector proteins as well as proteins that -$ DNA-dependent activator of IFN-regulatory factor (DAI), and/or via a positively and negatively modulate subsequent signaling. This poster high- pathway initiated by transmembrane Toll-like receptors (TLRs). All path- lights common and distinct components of these pathways that together ways culminate in activation of interferon regulatory factor (IRF) and lead to a highly orchestrated innate immune response to viral infection. 42!- -!, 42)& -Y$ Pathogen recognition: the cytosolic pathway and TYK2 kinases, respectively. IFN binding results in kinase Many viruses replicate in the cell cytoplasm after invading cells activation, receptor phosphorylation, and STAT protein recruit- )2!+ 2)0 by fusion either with the plasma membrane or with endosomal ment and tyrosine phosphorylation.
  • Inhibition of Polo-Like Kinase 1 During the DNA Damage Response Is Mediated Through Loss of Aurora a Recruitment by Bora

    Inhibition of Polo-Like Kinase 1 During the DNA Damage Response Is Mediated Through Loss of Aurora a Recruitment by Bora

    OPEN Oncogene (2017) 36, 1840–1848 www.nature.com/onc ORIGINAL ARTICLE Inhibition of Polo-like kinase 1 during the DNA damage response is mediated through loss of Aurora A recruitment by Bora W Bruinsma1,2,4,5, M Aprelia1,2,5, I García-Santisteban1,3, J Kool2,YJXu2 and RH Medema1,2 When cells in G2 phase are challenged with DNA damage, several key mitotic regulators such as Cdk1/Cyclin B, Aurora A and Plk1 are inhibited to prevent entry into mitosis. Here we have studied how inhibition of Plk1 is established after DNA damage. Using a Förster resonance energy transfer (FRET)-based biosensor for Plk1 activity, we show that inhibition of Plk1 after DNA damage occurs with relatively slow kinetics and is entirely dependent on loss of Plk1-T210 phosphorylation. As T210 is phosphorylated by the kinase Aurora A in conjunction with its co-factor Bora, we investigated how they are affected by DNA damage. Interestingly, we find that the interaction between Bora and Plk1 remains intact during the early phases of the DNA damage response (DDR), whereas Plk1 activity is already inhibited at this stage. Expression of an Aurora A mutant that is refractory to inhibition by the DDR failed to prevent inhibition of Plk1 and loss of T210 phosphorylation, suggesting that inhibition of Plk1 may be established by perturbing recruitment of Aurora A by Bora. Indeed, expression of a fusion in which Aurora A was directly coupled to Bora prevented DNA damage-induced inhibition of Plk1 activity, as well as inhibition of T210 phosphorylation. Taken together, these data demonstrate that DNA damage affects the function of Aurora A at multiple levels: both by direct inhibition of Aurora A activity, as well as by perturbing the interaction with its co-activator Bora.
  • PDF Hosted at the Radboud Repository of the Radboud University Nijmegen

    PDF Hosted at the Radboud Repository of the Radboud University Nijmegen

    PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/48948 Please be advised that this information was generated on 2021-09-28 and may be subject to change. MOLECULAR AND CELLULAR BIOLOGY, Feb. 2005, p. 1402–1414 Vol. 25, No. 4 0270-7306/05/$08.00ϩ0 doi:10.1128/MCB.25.4.1402–1414.2005 Copyright © 2005, American Society for Microbiology. All Rights Reserved. Divergent Mitochondrial and Endoplasmic Reticulum Association of DMPK Splice Isoforms Depends on Unique Sequence Arrangements in Tail Anchors† Rene´ E. M. A. van Herpen,1 Ralph J. A. Oude Ophuis,1 Mietske Wijers,1 Miranda B. Bennink,2 Fons A. J. van de Loo,2 Jack Fransen,1 Be´ Wieringa,1* and Derick G. Wansink1 Department of Cell Biology1 and Rheumatology Research and Advanced Therapeutics,2 Nijmegen Center for Molecular Life Sciences, University Medical Center, Nijmegen, The Netherlands Received 3 September 2004/Returned for modification 23 September 2004/Accepted 10 November 2004 Myotonic dystrophy protein kinase (DMPK) is a Ser/Thr-type protein kinase with unknown function, originally identified as the product of the gene that is mutated by triplet repeat expansion in patients with myotonic dystrophy type 1 (DM1). Alternative splicing of DMPK transcripts results in multiple protein isoforms carrying distinct C termini. Here, we demonstrate by expressing individual DMPKs in various cell ؊/؊ types, including C2C12 and DMPK myoblast cells, that unique sequence arrangements in these tails control the specificity of anchoring into intracellular membranes.
  • Abx651433 Datasheet.Pdf

    Abx651433 Datasheet.Pdf

    Datasheet Version: 3.0.0 Revision date: 23 Apr 2021 Human Protein Kinase R (PKR) Protein (Active) Catalogue No.:abx651433 SDS-PAGE analysis of recombinant Human PKR. Western blot analysis of recombinant Human PKR, using PKR antibody (abx128520). Gene sequencing extract of recombinant Human PKR. Binding activity of PKR with CDK1. For Reference Only Human Protein Kinase R (PKR) Protein (Active) is a recombinant active Human protein expressed in E. coli. Target: Protein Kinase R (PKR) Origin: Human Tested Applications: WB, SDS-PAGE v1.0.0 Abbexa LTD, Cambridge, UK · Phone: +44 (0) 1223 755950 · Fax: +44 (0) 1223 755951 1 of 3 Abbexa LLC, Houston, TX USA · Phone: +1 832 327 7413 Website: www.abbexa.com · Email: [email protected] Datasheet Version: 3.0.0 Revision date: 23 Apr 2021 Host: E. coli Conjugation: Unconjugated Form: Lyophilized Purity: > 80% Reconstitution: Reconstitute to the original concentration in ddH2O. If further dilutions are required, dilute in 20 mM Tris, 150 mM NaCl, pH 8.0, to a concentration of 0.1-1.0 mg/ml. Do not vortex. Storage: Store at 2-8 °C for up to one month. Store at -80 °C for up to one year. Avoid repeated freeze/thaw cycles. UniProt Primary AC: P19525 (UniProt, ExPASy) KEGG: hsa:5610 String: 9606.ENSP00000233057 Molecular Weight: Calculated MW: 35.8 kDa Observed MW: 32 kDa Possible reasons why the actual band size differs from the predicted band size: 1. Splice variants. Alternative splicing may create different sized proteins from the same gene. 2. Relative charge. The composition of amino acids may affect the charge of the protein.
  • Kinase Profiling Book

    Kinase Profiling Book

    Custom and Pre-Selected Kinase Prof iling to f it your Budget and Needs! As of July 1, 2021 19.8653 mm 128 196 12 Tyrosine Serine/Threonine Lipid Kinases Kinases Kinases Carna Biosciences, Inc. 2007 Carna Biosciences, Inc. Profiling Assays available from Carna Biosciences, Inc. As of July 1, 2021 Page Kinase Name Assay Platform Page Kinase Name Assay Platform 4 ABL(ABL1) MSA 21 EGFR[T790M/C797S/L858R] MSA 4 ABL(ABL1)[E255K] MSA 21 EGFR[T790M/L858R] MSA 4 ABL(ABL1)[T315I] MSA 21 EPHA1 MSA 4 ACK(TNK2) MSA 21 EPHA2 MSA 4 AKT1 MSA 21 EPHA3 MSA 5 AKT2 MSA 22 EPHA4 MSA 5 AKT3 MSA 22 EPHA5 MSA 5 ALK MSA 22 EPHA6 MSA 5 ALK[C1156Y] MSA 22 EPHA7 MSA 5 ALK[F1174L] MSA 22 EPHA8 MSA 6 ALK[G1202R] MSA 23 EPHB1 MSA 6 ALK[G1269A] MSA 23 EPHB2 MSA 6 ALK[L1196M] MSA 23 EPHB3 MSA 6 ALK[R1275Q] MSA 23 EPHB4 MSA 6 ALK[T1151_L1152insT] MSA 23 Erk1(MAPK3) MSA 7 EML4-ALK MSA 24 Erk2(MAPK1) MSA 7 NPM1-ALK MSA 24 Erk5(MAPK7) MSA 7 AMPKα1/β1/γ1(PRKAA1/B1/G1) MSA 24 FAK(PTK2) MSA 7 AMPKα2/β1/γ1(PRKAA2/B1/G1) MSA 24 FER MSA 7 ARG(ABL2) MSA 24 FES MSA 8 AurA(AURKA) MSA 25 FGFR1 MSA 8 AurA(AURKA)/TPX2 MSA 25 FGFR1[V561M] MSA 8 AurB(AURKB)/INCENP MSA 25 FGFR2 MSA 8 AurC(AURKC) MSA 25 FGFR2[V564I] MSA 8 AXL MSA 25 FGFR3 MSA 9 BLK MSA 26 FGFR3[K650E] MSA 9 BMX MSA 26 FGFR3[K650M] MSA 9 BRK(PTK6) MSA 26 FGFR3[V555L] MSA 9 BRSK1 MSA 26 FGFR3[V555M] MSA 9 BRSK2 MSA 26 FGFR4 MSA 10 BTK MSA 27 FGFR4[N535K] MSA 10 BTK[C481S] MSA 27 FGFR4[V550E] MSA 10 BUB1/BUB3 MSA 27 FGFR4[V550L] MSA 10 CaMK1α(CAMK1) MSA 27 FGR MSA 10 CaMK1δ(CAMK1D) MSA 27 FLT1 MSA 11 CaMK2α(CAMK2A) MSA 28
  • Muscle Wasting in Myotonic Dystrophies: a Model of Premature Aging

    Muscle Wasting in Myotonic Dystrophies: a Model of Premature Aging

    REVIEW published: 09 July 2015 doi: 10.3389/fnagi.2015.00125 Muscle wasting in myotonic dystrophies: a model of premature aging Alba Judith Mateos-Aierdi 1,2, Maria Goicoechea 1,2, Ana Aiastui 2,3, Roberto Fernández-Torrón 1,2,4, Mikel Garcia-Puga 5, Ander Matheu 5 and Adolfo López de Munain 1,2,4,6* 1 Neuroscience Area, Biodonostia Health Research Institute, San Sebastián, Spain, 2 CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain, 3 Cell Culture Platform, Biodonostia Health Research Institute, San Sebastián, Spain, 4 Department of Neurology, Hospital Universitario Donostia, San Sebastián, Spain, 5 Oncology Area, Biodonostia Health Research Institute, San Sebastián, Spain, 6 Department of Neuroscience, Universidad del País Vasco UPV-EHU, San Sebastián, Spain Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased Edited by: Jaime J. Carvajal, risk of developing tumors. From this point of view, DM1 could be described as Centro Andaluz de Biología del a progeroid syndrome since a notable age-dependent dysfunction of all systems Desarrollo, Spain occurs. The underlying molecular disorder in DM1 consists of the existence of Reviewed by: a pathological (CTG) triplet expansion in the 3’ untranslated region (UTR) of the John Charles McDermott, York University, Canada Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in Daniela Palacios, the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein Fondazione Santa Lucia, Italy 9 (CNBP/ZNF9) gene cause DM2.
  • Targeting the Hippo Pathway in Prostate Cancer: What's New?

    Targeting the Hippo Pathway in Prostate Cancer: What's New?

    cancers Review Targeting the Hippo Pathway in Prostate Cancer: What’s New? Kelly Coffey Solid Tumour Target Discovery Laboratory, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; [email protected] Simple Summary: Prostate cancer is the most commonly diagnosed cancer in men in the UK, accounting for the deaths of over 11,000 men per year. A major problem in this disease are tumours which no longer respond to available treatments. Understanding how this occurs will reveal new ways to treat these patients. In this review, the latest findings regarding a particular group of cellular factors which make up a signalling network called the Hippo pathway will be described. Accumulating evidence suggests that this network contributes to prostate cancer progression and resistance to current treatments. Identifying how this pathway can be targeted with drugs is a promising area of research to improve the treatment of prostate cancer. Abstract: Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ.
  • Double Stranded RNA Dependent Protein Kinase (PKR) and Type 2 Diabetes

    Double Stranded RNA Dependent Protein Kinase (PKR) and Type 2 Diabetes

    Pharmacy & Pharmacology International Journal Mini Review Open Access Double stranded RNA dependent protein kinase (PKR) and type 2 diabetes Abstract Volume 2 Issue 2 - 2015 Type 2 diabetes greatly increases the risk for developing cardiovascular and metabolic Arti Dhar,1 Priyanka Reddy,1 Audesh Bhat,2 disorders. Despite recent development in medical science, scientific understandings 3 on the root mechanisms of type 2 diabetes are still not fully understood, and such Indu Dhar 1Department of Pharmacy, Birla Institute of Technology and insufficient understanding contributes to the relative lack of effective treatments Sciences Pilani, India for such diseases. Protein Kinase R (PKR) is a serine threonine kinase activated 2Department of Microbiology & Immunology, University of during various stress conditions. Activation of PKR can increase reactive oxygen Saskatchewan, Canada species generation, inflammation and induce oxidative stress. In this review we 3Department of Pharmacology, University of Saskatchewan, discuss the potential role of PKR in type 2 diabetes, pathways activated by it and Canada the interrelationship between pathways activated. Specific and effective inhibitors of PKR are being developed and can become potential treatment for type 2 diabetes and Correspondence: Arti Dhar, Department of Pharmacy, Birla prevent many diseases. Institute of Technology and Sciences Pilani, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India, Tel Keywords: PKR, type 2 diabetes, inflammation, insulin resistance 04066303647, Email [email protected] Received: February 28, 2015 | Published: March 26, 2015 Abbreviations: PKR, protein kinase r; ER, endoplasmic reti- Type 2 diabetes is associated with elevated blood glucose levels, culum; Nfkb, nuclear factor kappa-light-chain-enhancer of activated b which in turn will affect plasma insulin levels.
  • Pre-Mrna Splicing and Human Disease

    Pre-Mrna Splicing and Human Disease

    Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Pre-mRNA splicing and human disease Nuno Andre´Faustino1,3 and Thomas A.Cooper 1,2,4 Departments of 1Pathology and 2Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; 3Graduate Program in Basic and Applied Biology, ICBAS, University of Oporto, Portugal The precision and complexity of intron removal during snRNP binds the branch site via RNA:RNA interactions pre-mRNA splicing still amazes even 26 years after the between the snRNA and the pre-mRNA (Fig. 1B). Spli- discovery that the coding information of metazoan genes ceosome assembly is highly dynamic in that complex is interrupted by introns (Berget et al. 1977; Chow et al. rearrangements of RNA:RNA, RNA:protein, and pro- 1977). Adding to this amazement is the recent realiza- tein:protein interactions take place within the spliceo- tion that most human genes express more than one some. Coinciding with these internal rearrangements, mRNA by alternative splicing, a process by which func- both splice sites are recognized multiple times by inter- tionally diverse protein isoforms can be expressed ac- actions with different components during the course of cording to different regulatory programs. Given that the spliceosome assembly (for example, see Burge et al. 1999; vast majority of human genes contain introns and that Du and Rosbash 2002; Lallena et al. 2002; Liu 2002). The most pre-mRNAs undergo alternative splicing, it is not catalytic component is likely to be U6 snRNP, which surprising that disruption of normal splicing patterns joins the spliceosome as a U4/U6 · U5 tri-snRNP (Villa can cause or modify human disease.
  • Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations

    Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations

    University of Pennsylvania ScholarlyCommons Departmental Papers (Vet) School of Veterinary Medicine 3-11-2016 Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations Kristin L. Gardiner University of Pennsylvania Louise Downs University of Pennsylvania Agnes I. Berta-Antalics University of Pennsylvania Evelyn Santana University of Pennsylvania Gustavo D. Aguirre University of Pennsylvania, [email protected] See next page for additional authors Follow this and additional works at: https://repository.upenn.edu/vet_papers Part of the Veterinary Medicine Commons Recommended Citation Gardiner, K. L., Downs, L., Berta-Antalics, A. I., Santana, E., Aguirre, G. D., & Genini, S. (2016). Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations. BMC Genomics, 17 (221), http://dx.doi.org/10.1186/s12864-016-2477-9 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/vet_papers/152 For more information, please contact [email protected]. Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations Abstract Background Mitotic terminally differentiated photoreceptors (PRs) are observed in early retinal degeneration (erd), an inherited canine retinal disease driven by mutations in the NDR kinase STK38L (NDR2). Results We demonstrate that a similar proliferative response, but of lower magnitude, occurs in two other early onset disease models, X-linked progressive retinal atrophy 2 (xlpra2) and rod cone dysplasia 1 (rcd1). Proliferating cells are rod PRs, and not microglia or Müller cells. Expression of the cell cycle related genes RB1 and E2F1 as well as CDK2,4,6 was up-regulated, but changes were mutation-specific.