The Multiple Therapeutic Targets of A20 (Advances in Experimental Medicine and Biology, 809)

Cover 1 Title Page 4 Copyright Page 5 Dedication Page 6 FOREWORD 7 PREFACE 9 ABOUT THE EDITOR ... 11 PARTICIPANTS 13 Table of Contents 17 ACKNOWLEDGMENTS 21 CHAPTER 1 A20-A BIPARTITE UBIQUITIN EDITING ENZYME WITH IMMUNOREGULATORY POTENTIAL 22 INTRODUCTION: A20, A CENTRAL INHIBITOR OF INFLAMMATION 22 THE MOLECULAR BASIS FOR A20-MEDIATED REGULATION OF NF-κB 23 A20: AN UNUSUAL UBIQUITIN EDITING PROTEIN 26 BEYOND UBIQUITIN EDITING, UBIQUITIN BINDING IS A NOVEL MECHANISM SUPPORTING THE NF-κB INHIBITORY FUNCTION OF A20 27 THE BROADER EFFECTS OF A20 28 THERAPEUTIC POTENTIAL OF A20: HOPES AND UNANSWERED QUESTIONS 29 PERSPECTIVES AND CONCLUSIONS 29 REFERENCES 30 CHAPTER 2 THE BIOLOGY OF A20-BINDING INHIBITORS OF NF-κB ACTIVATION (ABINS) 34 INTRODUCTION 34 IDENTIFICATION OF A20 BINDING INHIBITORS OF NF-κB (ABINs) 35 ABIN-1 35 Structure and Expression of ABIN-1 (TNIP-1/Naf1/VAN) 35 Biological Activities of ABIN-1 37 ABIN-1 in Disease 41 ABIN-2 42 Structure and Expression of ABIN-2 (TNIP-2/FLIP1) 42 Biological Activities of ABIN-2 43 ABIN-3 45 Structure and Expression of ABIN-3 (TNIP-3/LIND) 45 Biological Activities of ABIN-3 46 ABIN-3 in Disease 47 CONCLUSION 47 ACKNOWLEDGMENTS 47 REFERENCES 48 CHAPTER 3 THE BIOLOGY OF A20-LIKE MOLECULES 53 INTRODUCTION: THE BIOCHEMISTRY AND BIOLOGY OF UBIQUITIN 53 REGULATION OF NF-κB ACTIVATION BY UBIQUITIN 54 DEUBIQUITINATING ENZYMES 55 OTU FAMILY PROTEASES 56 A20 Subgroup of OTU Proteases 58 1. A20 58 2. Cezanne 59 3. TRABID 60 4. VCIP135 60 Otubains 60 PROTEINS CONTAINING A20-TYPE ZINC FINGERS 61 Rabex5 63 Znf216 64 AWP1 64 CONCLUSION 65 REFERENCES 65 CHAPTER 4 ANTI-VIRAL TETRIS: Modulation of the Innate Anti-Viral Immune Response by A20 69 INTRODUCTION 69 ACTIVATION OF THE RIG-I PATHWAY 70 UBIQUITINATION AND THE IFN PATHWAY 73 A20 AND THE IFN SIGNALING PATHWAY 75 REGULATION OF THE ANTIVIRAL RESPONSE BY UBIQUITINATION 77 CONCLUSION 78 ACKNOWLEDGMENTS 80 REFERENCES 80 CHAPTER 5 A20 EXPRESSING TUMORS AND ANTICANCER DRUG RESISTANCE 85 INTRODUCTION 86 OF SOLID TUMORS AND RESISTANCE TO CHEMOTHERAPY 86 THE ZINC FINGER PROTEIN A20 88 A20: THE BEAUTY OR THE BEAST? 90 ROLE OF A20 IN ANTICANCER DRUG RESISTANCE 90 Heightened Expression of A20 Contributes to Tumor Resistance to TRAIL 91 Decreased A20 Levels Promotes Resistance to O6-Alkylating Agents 93 CONCLUSION 97 ACKNOWLEDGMENTS 98 REFERENCES 98 CHAPTER 6 TRANSLATIONAL STUDIES OF A20 IN ATHEROSCLEROSIS AND CARDIOVASCULAR DISEASE 102 INTRODUCTION 103 OF NF-κB AND ATHEROGENESIS 104 DISCOVERY AND BIOLOGY OF THE ANTI-INFLAMMATORY TNF α INDUCED PROTEIN 3 (A20) 105 DUAL CYTOPROTECTIVE FUNCTION OF A20 IN ENDOTHELIAL CELLS 106 ATHEROPROTECTIVE FUNCTIONS OF A20 IN VASCULAR SMOOTH MUSCLE CELLS 108 PROOF OF PRINCIPLE: THERAPEUTIC EFFECTS OF A20 IN EXPERIMENTAL VASCULAR INJURY SYNDROMES 108 SYSTEMIC EFFECTS OF A20 THAT MAY IMPACT VASCULAR DISEASE 110 A20: A REGULATORY RESPONSE TO INFLAMMATION THAT GOES WEARY IN PRO-ATHEROGENIC ENVIRONMENTS 110 THERAPEUTIC POTENTIAL FOR A20 IN CARDIAC FAILURE 113 A20 AND ATHEROSCLEROSIS-FROM ENVIRONMENTAL/METABOLIC TO GENETIC RISK FACTORS 113 CONCLUSION 115 ACKNOWLEDGMENTS 116 REFERENCES 116 CHAPTER 7 A20-A BIOMARKER OF ALLOGRAFT OUTCOME: A Showcase in Kidney Transplantation 121 INTRODUCTION 121 APOPTOSIS AND ITS IMPACT ON TRANSPLANT OUTCOME 122 APOPTOSIS OF ALLO-ANTIGEN SPECIFIC T CELLS HELP IN PROMOTING TOLERANCE 124 CURRENT DIAGNOSTIC METHODS OF ALLOGRAFT MONITORING 124 PREDICTION: THE DIRECTION FOR NEW DIAGNOSTIC METHODOLOGIES 125 1. Molecular-Based Methods 126 Microarray 126 Quantitative Reverse Transcriptase Polymerase Chain Reaction 126 2. Cell-Based Methods 126 MOLECULAR DIAGNOSIS: A NON-INVASIVE DIAGNOSTIC APPROACH FOR ALLOGRAFT EVALUATION 127 Quantitative Reverse Transcriptase Polymerase Chain Reaction of Intra-Graft Biopsies 128 Quantitative Reverse Transcriptase Polymerase Chain Reaction of Urinary Cells 129 Quantitative Reverse Transcriptase Polymerase Chain Reaction of Peripheral Blood Cells 129 CONCLUSION 130 REFERENCES 130 CHAPTER 8 A20-AN OMNIPOTENT PROTEIN IN THE LIVER: Prometheus Myth Resolved? 135 INTRODUCTION 136 ACUTE AND CHRONIC CAUSES OF LIVER DISEASES 136 THE MOLECULAR BASIS FOR LIVER REGENERATION 137 1. Priming of Hepatocytes for Regeneration: Role of Cytokines and Transcription Factors 138 2. Progression beyond the Restriction Point in the G1 Phase of the Cell Cycle: Role of Growth Factors 138 3. Apoptosis of Excess Hepatocytes to Restore Optimal Liver Mass vs. Body Mass Ratio 139 ORTHOTOPIC LIVER TRANSPLANTATION: HOPES AND LIMITATIONS 139 THE "HEPATOPROTECTIVE" MOLECULE A20 140 ANIMAL MODELS OF LIVER INJURY UNRAVELING THE MULTIPLE HEPATO PROTECTIVE FUNCTIONS OF A20 141 1. A20 Knockout Mice Exemplify the Physiologic Anti-Inflammatory Function of A20 141 2. Overexpression of A20 in the Liver Prevents Acute Liver Failure and Death following Toxic Hepatitis: A Showcase for the Anti-Apoptotic and anti-Inflammatory Functions of A20 in Hepatocytes 142 3. Overexpression of A20 in the Liver Prevents Ischemia Reperfusion Injury by Containing Oxidative Stress and Necrotic Cell Death 144 4. Overexpression of A20 in the Liver Uniquely Promotes Hepatocyte Proliferation to Enhance Liver Regeneration: The Molecular Basis of Prometheus Myth 145 5. Benefits of Hepatic Overexpression of A20 in Animal Models of Liver Transplantation 147 THE MOLECULAR BASIS OF A20's HEPATOPROTECTIVE FUNCTIONS: A SYSTEMS BIOLOGY APPROACH UNRAVELING A20's IMPACT ON LIPID METABOLISM AND INSULIN SIGNALING 148 PERSPECTIVES 150 1. Beyond the Hepatocyte 150 2. Beyond Regeneration and Repair 150 CONCLUSION 150 ACKNOWLEDGMENTS 151 REFERENCES 151 CHAPTER 9 EMERGING ROLES FOR A20 IN ISLET BIOLOGY AND PATHOLOGY 158 INTRODUCTION 159 ISLETS OF LANGERHANS 159 A PRIMER ON DIABETES 161 GENETIC LINKS BETWEEN A20 AND DIABETES 161 A20 AND THE INTERSECTION WITH ISLET BIOLOGY AND PATHOLOGIES: A20 IS EXPRESSED BY PANCREATIC β-CELLS 163 A20 AND THE NF-κB SYSTEM IN ISLETS: EVIDENCE FOR NF-κB PROTEINS IN ISLETS 164 EVIDENCE FOR NF-κB ACTIVATION IN ISLETS 165 NF-κB CONTROLS ISLET INFLAMMATION 165 NF-κB IN ISLET TRANSPLANTATION 167 NF-κB BLOCKADE AS A THERAPEUTIC STRATEGY TO PROTECT ISLETS 167 A CONUNDRUM: NF-κB BLOCKADE CAN SENSITIZE ISLETS AND β-CELLS TO APOPTOTIC CELL DEATH 168 RESOLVING THE CONFLICTING DATA FOR NF-κB BLOCKADE IN ISLETS: APOPTOSIS AND LOSS OF A20 168 A20 AS A THERAPEUTIC TARGET FOR ISLET TRANSPLANTATION 169 NOVEL FUNCTIONS FOR A20 IN ISLET BIOLOGY 171 CONCLUSION 172 ACKNOWLEDGMENTS 173 REFERENCES 173 CHAPTER 10 SINGLE NUCLEOTIDE POLYMORPHISMS AT THE TNFAIP3/A20 LOCUS AND SUSCEPTIBILITY/RESISTANCE TO INFLAMMATORY AND AUTOIMMUNE DISEASES 180 INTRODUCTION 181 SINGLE NUCLEOTIDE POLYMORPHISMS 181 Definition and Nomenclature 181 Medical and Research Applications 185 A20 AND INFLAMMATORY/AUTOIMMUNE DISEASES 186 Coronary Artery Disease in Type 2 Diabetes 186 Rheumatoid Arthritis 187 Systemic Lupus Erythematosus 189 Type 1 Diabetes 191 Chronic Rhinosinusitis 192 Psoriasis 192 Celiac Disease and Inflammatory Bowel Disease 192 Rheumatic Heart Disease 193 Systemic Sclerosis 193 Behcet Disease 194 CONCLUSION 195 ACKNOWLEDGMENTS 196 REFERENCES 196 INDEX 201 Front Matter....Pages i-xxi A20—A Bipartite Ubiquitin Editing Enzyme with Immunoregulatory Potential....Pages 1-12 The Biology of A20-Binding Inhibitors of NF-κB Activation (ABINS)....Pages 13-31 The Biology of A20-Like Molecules....Pages 33-48 Anti-Viral Tetris: Modulation of the Innate Anti-Viral Immune Response by A20....Pages 49-64 A20 Expressing Tumors and Anticancer Drug Resistance....Pages 65-81 Translational Studies of A20 in Atherosclerosis and Cardiovascular Disease....Pages 83-101 A20—A Biomarker of Allograft Outcome: A Showcase in Kidney Transplantation....Pages 103-116 A20-An Omnipotent Protein in the Liver: Prometheus Myth Resolved?....Pages 117-139 Emerging Roles for A20 in Islet Biology and Pathology....Pages 141-162 Single Nucleotide Polymorphisms at the TNFAIP3/A20 Locus and Susceptibility/Resistance to Inflammatory and Autoimmune Diseases....Pages 163-183 Back Matter....Pages 185-188