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The Role of the Collapsin Response Mediator Protein 1

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The Role of the Collapsin Response Mediator Protein 1 THE ROLE OF THE COLLAPSIN RESPONSE MEDIATOR PROTEIN 1 (CRMP1) ON CELL MIGRATION AND INVASION IN GLIOMA by Jonah Shiroky A thesis submitted in partial fulfillment of the requirements for the degree of Master’s of Science, Division of Experimental Medicine McGill University, Montreal © Jonah Shiroky 2008 Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-56870-5 Our file Notre référence ISBN: 978-0-494-56870-5 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. TABLE OF CONTENTS TABLE OF CONTENTS ........................................................................................................................ 2 LIST OF FIGURES ................................................................................................................................... 4 ACKNOWLEDGEMENTS ....................................................................................................................... 5 ABBREVIATIONS ................................................................................................................................... 6 ABSTRACT ............................................................................................................................................. 7 RÉSUMÉ.................................................................................................................................................. 8 CHAPTER 1 : INTRODUCTION ......................................................................................................... 10 PREAMBLE .......................................................................................................................................... 11 CRMP SEQUENCE HOMOLOGY ............................................................................................................ 13 ALTERNATIVE SPLICING ...................................................................................................................... 14 DIFFERENTIAL EXPRESSION PATTERNS OF CRMP ISOFORMS .................................................................. 15 a) Central Nervous System (CNS) .................................................................................................... 15 b) Outside the CNS ......................................................................................................................... 16 STRUCTURE OF CRMP PROTEINS .......................................................................................................... 17 POSTTRANSLATIONAL MODIFICATIONS ................................................................................................. 18 a) Phosphorylation ......................................................................................................................... 18 b) Calpain Cleavage ....................................................................................................................... 19 c) Other Modifications .................................................................................................................... 20 BIOLOGICAL FUNCTIONS OF CRMP PROTEINS ....................................................................................... 20 a) Neurite outgrowth ...................................................................................................................... 20 b) The Sema3A (Collapsin-1) Pathway ............................................................................................ 24 c) CRMP and the Rho Pathway ....................................................................................................... 26 2 d) Neuronal Plasticity ..................................................................................................................... 26 e) Cell Migration ............................................................................................................................ 28 f) Neuronal Proliferation/Apoptosis................................................................................................. 30 IMPLICATIONS OF CRMP PROTEINS IN NEURODEGENERATIVE DISEASE .................................................. 31 THE ASSOCIATION OF CRMP PROTEINS WITH CANCER .......................................................................... 31 RATIONALE ........................................................................................................................................ 44 CHAPTER 2 : MATERIALS AND METHODS ................................................................................... 45 CHAPTER 3 : RESULTS...................................................................................................................... 54 IN VITRO EFFECTS OF CRMP ON GBM MIGRATION............................................................................... 55 INDIRECT IMMUNOFLUORESCENCE OF CRMP PROTEINS ........................................................................ 56 IN VIVO TUMOUR IMPLANTATIONS ....................................................................................................... 57 ASSOCIATION BETWEEN CRMP EXPRESSION AND SURVIVAL IN GBM PATIENTS ..................................... 58 EXPRESSION LEVELS OF CRMP IN GBM CELL LINES............................................................................. 59 CHAPTER 4 : DISCUSSION ................................................................................................................ 76 BIBLIOGRAPHY ................................................................................................................................. 84 3 LIST OF FIGURES Figure 1.1: Common properties of CRMP proteins .......................................................... 38 Figure 1.2: Model for Akt/GSK-3β/CRMP2 pathway in neurite outgrowth ...................... 40 Figure 1.3: CRMP1 and the Reelin Signaling Pathway .................................................... 42 Figure 3.1: Verification of CRMP overexpression ........................................................... 60 Figure 3.2: Analysis of cell proliferation ......................................................................... 62 Figure 3.3: Effect of CRMP1 on glioma cell migration .................................................... 64 Figure 3.4: Effects of other CRMP members on glioma cell migration ............................. 66 Figure 3.5: Indirect immunofluorescence of CRMP-transfected cell lines ........................ 68 Figure 3.6: In vivo tumour implantations ........................................................................ 70 Figure 3.7: The effect of CRMP1 and CRMP4 expression on GBM patient survival ........ 72 Figure 3.8: Real-time PCR analysis of CRMP expression ................................................ 74 Table 1.1: Sequence Homology of CRMP proteins.......................................................... 34 Table 1.2: Developmental Expression of CRMP Proteins ................................................ 36 Table 4.1: Chromosomal Alterations in GBM ................................................................. 82 4 ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisor, Josephine Nalbantoglu, who has been a huge source of support throughout my time in her laboratory. Her patience, insight and guidance have helped me become a better person and a better scientist. I am also grateful for her encouragement in my pursuit of a future in medicine. I thank her from the bottom of my heart. My colleagues have been a huge source of support and over the past two and half years. These individuals include: Cara Lau, Zaf Koty, Zivart Yasruel, David Huang, Patrick Fok, Nadia Houri, Vinit Srivastava, Raj Deol, Mike Sabbagh and Lisa “Smelly” Feldman. I would particularly like to thank Nancy Larochelle, for tolerating my endless questions regarding experimental procedures. Luyu
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