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The Cold-Inducible RNA-Binding Motif Protein 3 (RBM3) Prevents Cell Death Through Various Mechanisms

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The Cold-Inducible RNA-Binding Motif Protein 3 (RBM3) Prevents Cell Death Through Various Mechanisms The Cold-Inducible RNA-Binding Motif Protein 3 (RBM3) Prevents Cell Death Through Various Mechanisms Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Xinzhou Zhu aus Nanjing, Volksrepublik China Basel, 2016 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: PD. Dr. Sven Wellmann Prof. Dr. Josef Kapfhammer Prof. Dr. Anne Spang Basel, den 23. Februar 2016 Prof. Dr. Jörg Schibler Dekan der Philosophisch- Naturwissenschaftlichen Fakultät Table of contents PREFACE ............................................................................................................................................. 1 ABSTRACT .......................................................................................................................................... 2 1. INTRODUCTION .............................................................................................................................. 4 1.1 COLD RESPONSIVE PROTEINS .................................................................................................................. 4 1.1.1 Structure, evolution and spatial distribution ........................................................................... 5 1.1.2 Induction ................................................................................................................................. 9 1.1.2.1 Inducers ............................................................................................................................................ 9 1.1.2.2 Molecular mechanisms .................................................................................................................. 11 1.1.3 Molecular and cellular activities............................................................................................ 13 1.1.3.1 Regulation of post-transcriptional and translational events .......................................................... 13 1.1.3.2 Signaling pathways ......................................................................................................................... 15 1.1.3.3 Nuclear-cytoplasmic shuttling ........................................................................................................ 16 1.1.3.4 Cell cycle ......................................................................................................................................... 17 1.1.3.5 Anti-apoptosis ................................................................................................................................ 18 1.1.4 Biological functions and diseases .......................................................................................... 18 1.1.4.1 Brain disorders ............................................................................................................................... 18 1.1.4.2 Cancers ........................................................................................................................................... 20 1.1.4.3 Other functions .............................................................................................................................. 26 1.2 UNFOLDED PROTEIN RESPONSE (UPR) ................................................................................................... 30 1.2.1 Main signaling pathways of UPR .......................................................................................... 30 1.2.2 UPR and brain disorders ........................................................................................................ 31 1.2.3 Hypothermia and UPR ........................................................................................................... 31 1.3 MICRORNA (MIRNA) BIOLOGY ........................................................................................................... 32 1.3.1 Biogenesis of miRNA ............................................................................................................. 32 1.3.2 miRNA and brain disorders.................................................................................................... 32 1.3.3 Hypothermia, RBM3 and miRNA ........................................................................................... 33 1.4 SCOPE OF THE THESIS.......................................................................................................................... 34 2. MATERIALS AND METHODS .......................................................................................................... 36 2.1 ANIMALS AND ORGANOTYPIC HIPPOCAMPAL SLICE CULTURES ...................................................................... 36 2.2 CELL CULTURE AND MANIPULATION ....................................................................................................... 37 2.3 OXYGEN-GLUCOSE DEPRIVATION (OGD)................................................................................................. 37 2.4 PROTEIN EXTRACTION AND WESTERN BLOT ............................................................................................. 38 2.5 REAL-TIME RT-PCR ........................................................................................................................... 39 2.6 CELL VIABILITY ASSAY .......................................................................................................................... 40 2.7 FLUORESCENCE-ACTIVATED CELL SORTING (FACS) ................................................................................... 40 2.8 CO-IMMUNOPRECIPITATION (COIP) ...................................................................................................... 41 2.9 MASS SPECTROMETRY ........................................................................................................................ 41 2.10 IMMUNOSTAINING ........................................................................................................................... 42 2.11 PROXIMITY LIGATION ASSAY (PLA) ...................................................................................................... 42 2.12 STATISTICS ...................................................................................................................................... 43 3. RESULTS ....................................................................................................................................... 44 3.1 HYPOTHERMIA AND RBM3 PROMOTE CELL SURVIVAL ............................................................................... 44 3.1.1 Hypothermia prevents neural cell death in OGD model ........................................................ 44 3.1.2 RBM3 protects cells from H2O2-induced oxidative stress ...................................................... 47 3.1.3 Both hypothermia and RBM3 prevent ER stress-induced cell death ..................................... 48 3.2 HYPOTHERMIA AND RBM3 SUPPRESS PERK-EIF2Α-CHOP SIGNALING PATHWAY UNDER SUSTAINED ER STRESS ... 51 3.2.1 Hypothermia and RBM3 inhibit PERK-eIF2α-CHOP pathway ................................................ 51 3.2.2 Screening of RBM3 interacting partners ............................................................................... 57 3.2.3 NF90 is required for RBM3-mediated PERK inhibition ........................................................... 65 3.3 HYPOTHERMIA AND RBM3 REGULATE MIRNA EXPRESSION ....................................................................... 68 3.3.1 Hypothermia reduces the expression of pro-apoptotic miRNA ............................................. 68 3.3.2 RBM3 negatively regulates pro-apoptotic miRNAs ............................................................... 69 3.3.3 RBM3 positively regulates anti-apoptotic miRNAs ................................................................ 71 4. DISCUSSION ................................................................................................................................. 73 REFERENCES ..................................................................................................................................... 80 APPENDIX I ...................................................................................................................................... 98 APPENDIX II ................................................................................................................................... 101 ACKNOWLEDGEMENT .................................................................................................................... 104 CURRICULUM VITAE ....................................................................................................................... 105 Preface Parts of the INTRODUCTION (1.1 and 1.3.3) have been prepared as a literature review on RBM3 and CIRP, which is submitted to Cell Mol Life Sci for publication. The section 1.2.1 of the INTRODUCTION, parts of the MATERIALS AND METHODS section, chapter 3.1.3 and 3.2 of the RESULTS and parts of the DISCUSSION have been published in FASEB J (Zhu X et al., 2015). 1 Abstract Moderate hypothermia promotes the survival of neural cells in a wide range of brain disorders. During hypothermia, a subgroup of proteins including two homologues, RNA-binding motif protein 3 (RBM3) and cold-inducible RNA-binding protein (CIRP), is substantially induced when global translation is attenuated. Both RBM3 and CIRP do not only enhance cell viability
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