Clusterin, Part A (Advances in Cancer Research, Vol. 104) (Volume 104)

Advances in Cancer Research provides invaluable information on the exciting and fast-moving field of cancer research. In this Part A volume, outstanding and original reviews provide an overview and synthesis of the latest thoughts and findings relating to Clusterin. Chapters include the shifiting balance between CLU Forms during tumor progression, uclear CLU and the fate of the cell, and Oxidative stress in malignant progression. Cover Page 1 Title Page 2 Copyright 5 Contents 6 Contributors 10 Introduction 12 Introduction 12 Acknowledgments 18 References 18 Clusterin (CLU): From One Gene and Two Transcripts to Many Proteins 20 Introduction 21 CLU Gene Organization, Promoter Region, and Transcription Products 22 CLU Protein Forms 29 Conclusions 30 Acknowledgments 31 References 32 The Shifting Balance Between CLU Forms During Tumor Progression 35 Introduction 35 Shifting of Cell Metabolism in Tumorigenesis 36 Shifting of CLU Forms During Tumor Progression 37 Concluding Remarks 41 Acknowledgments 41 References 41 Regulation of Clusterin Activity by Calcium 43 Introduction 44 Ca2+ Signal 44 Ca2+ Contribution to CLU-Mediated Effects 45 Ca2+ Influx Through TRPM-2 Channels and CLU Location 47 Ca2+ And Cell Proliferation 48 Is CLU a Ca2+-Dependent Pro- or Antiapoptotic Gene? 49 Ca2+ Homeostasis and CLU Transcription 53 CLU Translocations in Response to Ca2+ Signal 57 ER Stress, Unfolded Protein Response, Ca2+, and CLU 58 Ca2+, Clusterin, and DNA Repair 60 Conclusions 61 Acknowledgments 62 References 62 Nuclear CLU (nCLU) and the Fate of the Cell 69 Introduction: Where is CLU? 70 Preliminary Remarks Before Dealing with nCLU: The Possible Action of sCLU as Differentiating Agent 72 A Brief History of nCLU 74 CLU Expression and Localization in the Regressing Rat Ventral Prostate 75 CLU was Found Positively Linked to Apoptosis and Negatively Linked to Proliferation: The Early Years (1993-1995) 77 CLU and Follicular Atresia, Another Model of Tissue Involution Linked to Apoptosis 79 CLU Expression was Found Associated to Nonapoptotic Cell Death 79 CLU Expression was Found Associated to Lesions in Central and Peripheral Nervous System 80 Increased CLU Expression is Linked to Inhibition of Proliferation and Induction of Cell Differentiation 81 Early Studies on Translational Upregulation of CLU During Apoptosis: The Role of NF1 82 CLU Gene Expression and Cell Death Induced by Vitamin D (Calcitriol) and Tamoxifen (Tam): Implication in Chemioresistance 83 Early Observations: CLU Expression is Induced by TGF-Beta 1; NF-Kappa B Inhibitors Blocked the Secretion of CLU 84 1996: nCLU Finally Appears in the Literature 85 A Role For nCLU in the Nucleus: Binding to Ku70 87 nCLU Today: The Dark Side of the Moon Revealed 88 The Molecular Mechanisms of Production of nCLU are Still Sketchy 90 In the End: Is Targeting of CLU to the Nucleus an Experimental Artifact? 93 Conclusions 94 Acknowledgments 95 References 95 The Chaperone Action of Clusterin and Its Putative Role in Quality Control of Extracellular Protein Folding 99 Introduction 100 Clusterin as a Chaperone 102 Molecular Chaperones 102 The In Vitro Chaperone Action of Clusterin 103 In Vivo Insights into the Chaperone Action of Clusterin 106 Associations of Clusterin with Extracellular Protein Deposits 106 Mouse Models 107 Other Extracellular Chaperones (ECs) and a Model For Quality Control (QC) of Extracellular Protein Folding 108 Other ECs 109 Haptoglobin 109 alpha2-Macroglobulin 110 A Family of Functionally Related ECs 111 A Model for QC of Extracellular Protein Folding 112 Future Research Directions 113 Refinement of In Vitro Conditions Used to Study the Chaperone Action of Clusterin 113 Identification of Endogenous Chaperone Client Proteins 114 Clusterin-Client Protein Complexes 115 Receptors 115 Conclusion 117 References 117 Cell Protective Functions of Secretory Clusterin (sCLU) 125 Introduction 125 sCLU-A Component of High-Density Lipoproteins 126 sCLU in Apoptosis-Signaling Toward Cell Survival? 127 sCLU in the Removal of Dead Cells and Cellular Debris 130 sCLU in Immune Modulation 133 Role of sCLU in Amyloid Beta (Abeta) Clearance in M. Alzheimer 136 Conclusions and Perspectives 138 References 139 Clusterin: A Multifacet Protein at the Crossroad of Inflammation and Autoimmunity 149 Introduction 150 Inflammation, the Danger Signal, and Autoimmunity 151 Immune System Homeostasis and Regulation: The Common Purpose of Autoimmunity and Cancer 152 Inflammation 152 CLU: A Complement Inhibitor and an Acute-Phase Protein 153 Protective Effect of CLU Independently of Complement Activation 155 CLU Interaction with Ig 155 CLU and Immune Cells 156 Dendritic Cells: At The Crossroad Of Innate And Adaptative Immunity 156 CLU and NF-kappaB 157 Cellular Regulation Through Apoptosis 158 From Acute to Chronic Inflammation: A Place for Oxidative Burst, Nitric Oxide 159 The Place and Role of CLU In Autoimmune Diseases (Table I and Fig. 1) 160 Rheumatoid Arthritis 160 Cellular Dysregulation in Synovitis 164 Cartilage 165 CLU at the Crossroad of Autoimmune Reactions in the Joint 166 Systemic Lupus Erythematosus 168 CLU Implication in SLE 168 Diabetes 170 Juvenile Dermatomyositis 171 Myocarditis 171 Concluding Remarks 171 References 173 Oxidative Stress in Malignant Progression: The Role of Clusterin, A Sensitive Cellular Biosensor of Free Radicals 181 Introduction 182 Molecular Effects of Altered Oxidative Load in Human Cells 183 Oxidative Injury in Ageing and Age-Related Diseases 187 Oxidative Stress in Malignant Progression 189 Clusterin as a Sensitive Cellular Biosensor of Oxidative Stress 191 Clusterin Regulation and Function at the Cellular Level as a Response to Free Radicals and Their Derivatives 191 Implication of Clusterin in States of Increased Organismal Oxidative Stress 194 What Can We Learn from the Functional Similarities Between Clusterin and Its Distal Homologues, the Small-Heat Shock Proteins? 199 Concluding Remarks-Perspectives 201 Acknowledgment 205 References 205 Index 221 Content: Series Editors Pages i-iii Copyright Page Page iv Contents Pages v-viii Contributors to Volume 104 Pages ix-x Chapter 1 Introduction Review Article Pages 1-8 Saverio Bettuzzi Chapter 2 Clusterin (CLU): From One Gene and Two Transcripts to Many Proteins Review Article Pages 9-23 Federica Rizzi, Mariangela Coletta, Saverio Bettuzzi Chapter 3 The Shifting Balance Between CLU Forms During Tumor Progression Review Article Pages 25-32 Sabina Pucci, Saverio Bettuzzi Chapter 4 Regulation of Clusterin Activity by Calcium Review Article Pages 33-58 Beata Pajak, Arkadiusz Orzechowski Chapter 5 Nuclear CLU (nCLU) and the Fate of the Cell Review Article Pages 59-88 Saverio Bettuzzi, Federica Rizzi Chapter 6 The Chaperone Action of Clusterin and Its Putative Role in Quality Control of Extracellular Protein Folding Review Article Pages 89-114 Amy Wyatt, Justin Yerbury, Stephen Poon, Rebecca Dabbs, Mark Wilson Chapter 7 Cell Protective Functions of Secretory Clusterin (sCLU) Review Article Pages 115-138 Gerd Klock, Markus Baiersdörfer, Claudia Koch-Brandt Chapter 8 Clusterin: A Multifacet Protein at the Crossroad of Inflammation and Autoimmunity Review Article Pages 139-170 Géraldine Falgarone, Gilles Chiocchia Chapter 9 Oxidative Stress in Malignant Progression: The Role of Clusterin, A Sensitive Cellular Biosensor of Free Radicals Review Article Pages 171-210 Ioannis P. Trougakos, Efstathios S. Gonos Index Pages 211-215

The biological function of clusterin (CLU, also known as ApoJ, SGP2, TRPM2, CLI) has been puzzling researchers since its discovery and characterization in the early 1980s. Approaches such as cloning, expression and functional characterization of the different protein products generated by the CLU gene have now produced a critical mass of information of tremendous biological importance that are teaching us an important lesson in molecular biology of gene expression regulation. This volume brings together the contributions of top researchers in the field, providing an overview and synthesis of the latest thought and findings relating to CLU.

Contains information on the field of cancer research. This title provides an overview and synthesis of the thoughts and findings relating to Clusterin. It includes the chapters such as the shifting balance between CLU Forms during tumor progression, unclear CLU and the fate of the cell, and oxidative stress in malignant progression.