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Ludwig Institute for Cancer Research & Department of Cell & Molecular Biology NR4A ORPHAN NUCLEAR RECEPTORS in IMMEDIATE

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Ludwig Institute for Cancer Research & Department of Cell & Molecular Biology NR4A ORPHAN NUCLEAR RECEPTORS in IMMEDIATE Ludwig Institute for Cancer Research & Department of Cell & Molecular Biology NR4A ORPHAN NUCLEAR RECEPTORS IN IMMEDIATE EARLY REGULATION OF RETINOID SIGNALING AND NEUROPROTECTION Nikolaos Volakakis Stockholm 2010 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Larserics Digital Print AB. © Nikolaos Volakakis, 2010 ISBN 978-91-7409-901-0 2 ABSTRACT NR4A receptors show distinct properties that make them unique within the family of nuclear receptors. They lack a ligand-binding cavity and a canonical coactivator-binding site and they are induced both in vivo and in vitro in an immediate early way by an extremely wide repertoire of substances/conditions. Apart from their specific roles during development, they play crucial, yet not fully charazterized, roles in sensing of and responding to changes in the cellular environment. In paper I, we provide novel insights into the mechanism of NR4A-mediated transcription by identifying an alternative coactivator-binding surface that is unique to the NR4A family of nuclear receptors. We also report a link between NR4A transcriptional activity and protein turnover and identify protein sequence differences between the NR4A receptor members that may account for their differential transcriptional activity. In paper II, we provide evidence suggesting that NR4A receptors can influence signaling events of other nuclear receptors via inducing the expression of fatty acid binding protein 5. Specifically, NR4A receptors can enhance retinoic acid-induced signaling of the peroxisome proliferator-activated receptor and docosahexaenoic acid-induced activation of the retinoid X receptor. In paper III, we demonstrate that NR4A proteins are induced by cyclic AMP response element binding protein (CREB) in neurons exposed to excitotoxic and oxidative insults and that they function as mediators of CREB-induced neuronal survival by inducing the expression of a battery of neuroprotective genes. Moreover, we show that mice with null mutations in three out of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes and increased vulnerability in the hippocampus after treatment with the excitotoxin kainic acid. In summary, we show that NR4A receptors utilize a distinct surface to bind coactivators, that they can influence signaling by two other nuclear receptors by upregulating a fatty acid binding protein and that they are essential mediators of neuroprotection after exposure to neuropathological stress. 3 LIST OF PUBLICATIONS This thesis is based on the following original papers, referred to in the text by their Roman numerals: I. Nikolaos Volakakis, Michal Malewicz, Banafsheh Kadkhodaei, Thomas Perlmann (2006). Characterization of the Nurr1 ligand-binding domain co- activator interaction surface. Journal of Molecular Endocrinology. Vol 37: 317-326. II. Nikolaos Volakakis, Eliza Joodmardi, Thomas Perlmann (2009). NR4A orphan nuclear receptors influence retinoic acid and docosahexaenoic signaling via up-regulation of fatty acid binding protein 5. Biochemical and Biophysical Research Communications. Vol 390 (4): 1186-91. III. Nikolaos Volakakis, Banafsheh Kadkhodaei, Eliza Joodmardi, Karin Wallis, Lia Panman, Jessica Silvaggi, Bruce M. Spiegelman, Thomas Perlmann (2010). NR4A orphan nuclear receptors trigger a neurorotective pathway induced by elevatated cyclic AMP. Manuscript submitted for publication. Other papers not included in this thesis: Stina Friling, Elisabet Andersson, Lachlan Thompson, Marie Jönsson, Josephine Hebsgaard, Evanthia Nanou, Zhanna Alekseenko, Ulrika Marklund, Susanna Kjellander, Nikolaos Volakakis, Outi Hovatta, Abdeljabbar El Manira, Anders Björklund, Thomas Perlmann, Johan Ericson (2009). Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proceedings of the National Academy of Sciences of the Unites States of America. Vol 106 (18): 7613-18. 4 TABLE OF CONTENTS LIST OF ABBREVIATIONS 6 A. INTRODUCTION 10 1 Nuclear Receptors 10 2 The NR4A subfamily of Nuclear Receptors 16 3 NR4A receptors in disease 17 4 NR4A receptor knockout mice 23 5 DNA binding of NR4A receptors 25 6 The transcriptional activity of NR4A receptors 27 7 The immediate early aspect of NR4A receptors 36 8 NR4A receptors in the CNS 38 9 NR4A receptors in neuroprotection 42 B. RESULTS AND DISCUSSION 44 1 Paper I: The coactivator-binding site of Nurr1 44 2 Paper II: FABP5 as a NR4A target gene 46 3 Paper III: NR4A receptor-mediated neuroprotection 51 C. ACKNOWLEDGEMENTS 64 D. REFERENCES 65 5 LIST OF ABBREVIATIONS 0-9 CCCP: carbonyl cyanide m-chlorphenyl hydrazone 3-NP: 3-nitropropionic acid CDK: cyclin-dependent kinase 4E-bp2: eukaryotic translation initiation CNS: central nervous system factor 4E binding protein 2 CNTF: ciliary neurotrophic factor 6-MP: 6-mercaptopurine COMT: catechol-O-methyltransferase 6-OHDA: 6-hydroxy-dopamine COUP-TF: chicken ovalbumin upstream promoter-transcription factor A COX-2: cyclooxygenase-2 CRABP: cellular retinoic acid binding A: adenine protein AA: amino acid CRE: cAMP response element AADC: aromatic L-amino acid CREB: CRE binding protein decarboxylase CREM: CRE modulator AAV: adeno-associated virus CRH: corticotropin-releasing hormone Abl2: Abelson murine leukemia viral CRIF1: CR6-interacting factor 1 oncogene homolog 2 CtBP: C-terminal binding protein ACTH: adrenocorticotropic hormone CTCL: cutaneous T cell lymphoma AcvrIIb: activin A receptor, type IIB Adcyap1: adenylate cyclase activating D peptide 1 Adm: adrenomedullin DAP3: death-associated protein 3 AF: activation function DAT: dopamine transporter Ala: alanine DBD: DNA binding domain AMPK: adenosine monophosphate kinase DCC: deleted in colorectal carcinoma AR: androgen receptor Ddx6: DEAD box polypeptide 6 Arg: arginine DG: dentate gyrus ASC-2: anterior suture cataract-2 DHA: docosahexaenoic acid Asn: asparagine DHR38: Drosophila hormone receptor 38 DISC: death-inducing signaling complex B Dlk1: delta-like 1 homologue DMN: dorsal motor nucleus Bcl2: B cell lymphoma 2 DN: dominant negative BDNF: brain-derived neurotrophic factor DNA-PK: DNA-dependent protein kinase bp: base pairs DOPAC: dihydroxy phenylacetic acid Brn3: brain 3 DR: direct repeat ds: double-stranded C Dyrk1A: dual specificity tyrosine phosphorylation-regulated kinase 1A C: cytosine C/EBP: CCAAT/enhancer binding protein E CBP: CREB-binding protein c-FLAR: CASP8 and FADD-like apoptosis EBV: Epstein-Barr virus regulator EcR: ecdysteroid receptor CAMK: calcium/calmodulin-dependent EcRE: ecdysone response element protein kinase EGF: epidermal growth factor cAMP: cyclic adenosine monophosphate EMC: extraskeletal myxoid chondrosarcoma 6 En: engrailed HPA: hypothalamus-pituitary-adrenal ER: estrogen receptor HPG: hypothalamus-pituitary-gonadal ERK: extracellular signal-regulated kinase HPV: human papilloma virus ERR: estrogen-related receptor HRE: hypoxia response element ES: embryonic stem HSDx hydroxysteroid dehydrogenase x EWS: Ewing sarcoma Hsp: heat shock protein Ex: embryonic day x HSV: herpes simplex virus Hx: helix x F I FA: fatty acid FABP: fatty acid binding protein IAP1: inhibitor of apoptosis protein 1 FAIM: Fas apoptotic inhibitory molecule ICAM: intercellular adhesion molecule Fas: fatty acid synthase Igf2bp1: insulin-like growth factor 2 mRNA FasL: Fas ligand binding protein 1 FGF: fibroblast growth factor IFN: interferone FLIP: Fas-associated death domain-like ig: intragastric interleukin-1-beta-converting enzyme IL: interleukin inhibitory protein INSL3: insulin-like 3 Fox: forkhead box protein ip: intraperitoneal Fra-2: fos-related antigen-2 iv: intravenous FSH: follicle stimulating hormone J G JNK: c-Jun N-terminal kinase G: guanidine GABA: gamma-amino byturic acid K GFP: green fluorescent protein GIOT-1: gonadotropin inducible transcription KA: kainic acid repressor -1 kb: kilobases Gja1: gap-junction protein α1 kDa: kilo Dalton Glu: glutamic acid Klhl1: kelch-like protein 1 GLUT4: glucose transporter 4 GnRH: gonadotropin-releasing hormone L Gpam: glycerol-3 phosphate acyltransferase GR: glucocorticoid receptor LBD: ligand-binding domain GSK: glycogen synthase kinase LBP: ligand-binding pocket GST: glutathione S-transferase LDL: low-density lipoprotein GTP: guanidine triphosphate Lef-1: lymphoid enhanced binding factor 1 GTPCH: GTP cyclohydrolase Leu: leucine LH: luteinizing hormone H LIF: leukemia inhibitory factor LIMK1: LIM domain kinase 1 HAT: histone acetyltransferase LRH1: human liver receptor homolog 1 HBV: hepatitis B virus LSD1: lysine-specific demethylase HD: Huntington’s disease LTR: long terminal repeat HDAC: histone deacetylase LXR: liver X receptor HEK293: human embryonic kidney 293 Lys: lysine HIF-1: hypoxia inducible factor-1 HIV-1: human immunodeficiency virus-1 M HNF4: hepatocyte nuclear factor 4 7 mAChRs: muscarinic acetylcholine receptors PCR: polymerase chain reaction MAPK: mitogen-activated protein kinase PD: Parkinson’s disease MC1R: melanocortin-1 receptor PDBu: phorbol 12,13 dibutyrate MCAO: middle cerebral artery occlusion PDGF: platelet-derived growth factor MCP-1: monocyte chemoattractive protein-1 PDK-1: phosphoinositide-dependent kinase-1 MEF: myocyte enhancer factor PELP1: proline-, glutamic acid-, leucine-rich MEFs: mouse embryonic fibroblasts protein 1 MEHP: mono-(2-ethylhexyl) phthalate PGC-1: PPAR gamma coactivator-1 MEKK1: mitogen-activated protein kinase PGx: prostaglandin x kinase kinase 1 PHD: prolyl hydroxylase domain MIP-1: macrophage inflammatory
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