BCL‑2 Protein Family (eBook)

Claudio Hetz received his BA in Biotechnology Engineering from the University of Chile in 2000. In his PhD work with Claudio Soto at Serono Pharmaceutical Research Institute, Geneva, he showed that Prion pathogenesis involves endoplasmic reticulum stress responses and apoptosis. In 2004 he joined as a postdoctoral fellow Stanley Korsmeyer’s lab at Dana‑Farber Cancer Institute, a pioneer in the apoptosis field. Together they discovered new functions of the BCL‑2 family in organelle physiology. Dr. Hetz followed his projects in Laurie Glimcher’s lab at Harvard. During this period he expanded his studies on neurodegeneration, addressing the connection between apoptosis and the unfolded protein response in vivo. Since 2007 he is an Assistant Professor at the University of Chile and adjunct professor at Harvard. His lab uses animal models to investigate the signaling responses involved in protein misfolding disorders and the role of the BCL‑2 protein family in stress conditions. He was recently awarded with the TWAS‑ROLAC Young Scientist Prize, also as finalist with the Eppendorf and Science Award in Neurobiology, and other important recognitions.

Title Page 3
Copyright Page 4
FOREWORD 5
PREFACE 6
ABOUT THE EDITOR... 8
PARTICIPANTS 9
Table of Contents 12
Chapter 1 Homeostatic Functions of BCL-2 Proteins beyond Apoptosis 15
Introduction 15
Mitochondrial Energy Metabolism 17
Functional Interaction of BCL-XL and VDAC in Regulation of Mitochondrial Outer Membrane Permeability to Metabolites 18
Deciphering Calcium Signals: BCL-2 Family and the ER-Mitochondria Cross Talk 19
Remodeling the Mitochondrial Membrane: BCL-2 Family Members and Mitochondrial Dynamics 21
BCL-2 Family and Mitochondrial Fuel Metabolism: A Role for BAD in Glucose Sensing 24
Autophagy 28
Protein Quality Control and the Unfolded Protein Response 30
The Sensors and Effectors Downstream of UPR 31
The Outcomes of Signaling Downstream of UPR 31
Physiologic Roles for BCL-2 Family Proteins in Cell Cycle Checkpoints, Differentiation and DNA Damage Response 33
BCL-2 Family and Cell Cycle Checkpoints 33
Differentiation 35
has not been formally examined. 36
Conclusion 37
References 37
Chapter 2 Alternative Functions of the BCL-2 Protein Family at the Endoplasmic Reticulum 47
Introduction 47
The BCL-2 Protein Family and the Unfolded Protein Response 48
Chronic ER Stress and BH3-Only Proteins 51
The BCL-2 Protein Family and the Calcium Rheostat 53
Autophagy and the BCL-2 Protein Family of Proteins 54
The BCL-2 Protein Family and ER Morphogenesis 56
Conclusion 56
References 57
Chapter 3 BH3-Only Proteins and Their Effects on Cancer 62
Introduction 62
Categories of BCL-2 Family Proteins and Their Apoptotic Functions 63
Multidomain Proapoptotic Members 63
Anti-Apoptotic BCL-2 Family Members 64
Proapoptotic BH3-Only Function 64
Regulation of Various BH3-Only Proteins and Cell Stress Sensing 66
BH3-Only Proteins and Cancer Development 68
BH3-Only Proteins and Chemotherapy Response and Resistance 70
BH3-Only Mimetic Drugs 71
Conclusion 71
References 71
Chapter 4 Endoplasmic Reticulum Stress and BCL-2 Family Members 77
Introduction 77
UPR: The Good and the Evil Side 79
UPR and BCL-2 Family Members 80
Autophagy, UPR and BCL-2 Family Members 83
Conclusion 85
References 86
Chapter 5 Targeting Survival Pathways in Lymphoma 90
Introduction 90
BCL-2 Proteins and Apoptosis 91
Pharmacologic Modulation of BCL-2 Proteins and Apoptosis 92
Modified Peptides 93
Small Molecule Inhibitors of Anti-Apoptotic Proteins 93
HA14-1 and Analogs 93
BH3I-2 and Analogs 94
Antimycin and Analogs 95
Gossypol and Derivatives 95
GX015-070 (Obatoclax Mesylate) 97
ABT-737 and ABT-263 98
Antisense Strategies 100
Targeting TRAIL 101
Agonistic Antibodies 101
Ligand Based Receptor Agonism 101
BCL-2 Proteins and Non-Apoptotic Cell Death 101
Conclusion 102
References 102
Chapter 6 The Interplay between BCL-2 Family Proteins and Mitochondrial Morphology in the Regulation of Apoptosis 108
Introduction 108
An Historical Perspective on the Proteins of the BCL-2 Family 108
Apoptotic Pathways 109
BCL-2 Family 109
BH Domains and Molecular Interaction 111
BCL-2 Antiapoptotic Proteins 111
BCL-2 and BCL-XL 111
Bcl-W 112
Mcl-1 113
Bfl-1/A1 113
BCL-2 Proapoptotic Proteins 114
Bax and Bak 114
BH3 Only Proteins 114
Mitochondrial Shape and Apoptosis 117
Mitochondrial Morphology: An Equilibrium between Fusion and Fission 117
Mitochondrial Fragmentation during Apoptosis: The Role of BCL-2 Family Members 119
Mitochondrial Ultrastructural Changes during Apoptosis 120
Conclusion 120
References 120
Chapter 7 Noncanonical Functions of BCL-2 Proteins in the Nervous System 126
Introduction 126
Extending the Traditional View of BCL-2 Family Proteins 127
Challenging the Traditional BCL-2 Family Model 128
BCL-2 Family Proteins in the Nervous System 129
When Anti-Death BCL-2 Proteins Become Pro-Death 130
When Pro-Death BCL-2 Proteins Protect Neurons 131
Protection Predicts New Functions with a Seizure 133
BCL-2 Family Proteins Regulate Synaptic Activity 134
Conclusion 135
References 135
Chapter 8 Mitochondria on Guard: Role of Mitochondrial Fusion and Fission in the Regulation of Apoptosis 141
Introduction 141
Regulation of Mitochondrial Fusion and Fission 141
Mitochondrial Fusion 141
Mitochondrial Fission 142
Mitochondrial Network Dynamics and Cell Homeostasis 143
Mutual Relations between Cell Homeostasis and Mitochondrial Network Dynamics 143
Mitochondrial Dynamics and Early Development 144
Role of Mitochondrial Dynamics in Cell Death 144
Mechanism of the OMM Permeabilization: A Vital Role for Mitochondrial Fusion and Fission? 146
Opal and Cristae Remodeling 146
Mitochondrial Morphogenesis and the OMM Permeabilization 147
Emerging Evidence for the Role of BCL-2 Family Proteins in the Regulation of Mitochondrial Network Dynamics in Healthy Cells 148
Conclusion 150
References 150
Index 153