Note: Intro -- Foreword -- Preface -- Contents -- Contributors -- Chapter 1: Historical Perspective: The Seven Ages of Cell Death Research -- 1.1 Infancy 1665-1972 -- 1.2 Childhood: Beyond Morphology and Towards Mechanism 1973-1988 -- 1.3 Adolescence-Coming of Age-First Clues to Mechanism, and the Link to Human Disease 1988-1992 -- 1.4 Adulthood: More of the Mechanism, Evolutionary Conservation 1992-1994 -- 1.5 Middle-Aged Expansion 1994-2005 -- 1.6 Maturity: Translation 2005-Present -- 1.7 Old Age: Senility, or Just Eccentricity? -- References -- Chapter 2: The Intrinsic Apoptotic Pathway -- 2.1 Introduction -- 2.2 The Discovery of the Mitochondrial Pathway, a Historical Overview -- 2.3 Mechanism of Cytochrome c-Mediated Caspase Activation -- 2.3.1 Nucleotide, Apaf-1, and Apoptosome -- 2.3.2 A Unique Mechanism for Caspase-9 Activation -- 2.3.3 IAP Proteins and Their Antagonists -- 2.3.4 Mitochondria as the Apoptosis Headquarters -- 2.4 Cross Talk of the Mitochondrial Pathway with Other Apoptotic Pathways -- 2.4.1 Cross Talk with the Death Receptor Pathway -- 2.4.2 Apoptosis Involving Caspase-2 Activation -- 2.5 Regulation in the Downstream of Cytochrome c Release -- 2.5.1 Nucleotide Exchange of Apaf-1 -- 2.5.2 Protein Phosphorylation -- 2.5.3 Other Factors Regulating Apoptosome Function -- 2.6 Noncanonical Functions of the Mitochondrial Pathway -- 2.6.1 Settling the Debate of Point of No-Return -- 2.6.2 Non-death Functions of Caspases -- 2.6.3 The Unsolved Question of Fate Determination -- 2.6.4 Noncanonical Functions of the Canonical Components of the Mitochondrial Pathway -- 2.7 Concluding Remarks -- References -- Chapter 3: Molecular Basis of Cell Death Programs in Mature T Cell Homeostasis -- 3.1 Forms of T Cell Death -- 3.1.1 Apoptosis -- 3.1.2 Non-apoptotic Cell Death -- 3.2 Central Role of Caspases in Apoptosis. , 3.3 Extrinsic, Death Receptor-Induced Apoptosis and Necroptosis -- 3.3.1 TNFR Superfamily Death Receptors -- 3.3.1.1 FAS -- 3.3.1.2 TNFR1 -- 3.3.1.3 TRAIL-R1 and TRAIL-R2 -- 3.3.2 Restimulation-Induced Cell Death -- 3.4 Intrinsic, Mitochondrion-Dependent Apoptosis -- 3.4.1 BCL-2 Family Proteins -- 3.4.2 Role of Mitochondrial Intermembrane Proteins -- 3.4.3 APAF-1 Apoptosome -- 3.4.4 Cytokine Withdrawal-Induced Death -- 3.5 Diseases of Failed Lymphocyte Apoptosis -- 3.5.1 Autoimmune Lymphoproliferative Syndrome -- 3.5.2 X-Linked Lymphoproliferative Disease-1 -- 3.6 Concluding Remarks -- References -- Chapter 4: Bcl-2 Family and Their Therapeutic Potential -- 4.1 Introduction and Overview -- 4.2 Bcl-2 Family, Cell Death, and Diseases -- 4.2.1 Apoptosis and Cancer -- 4.2.2 Bcl-2 Family in Apoptosis -- 4.2.3 Bcl-2 Family and Cancer -- 4.3 Bcl-2 Family Portrait -- 4.4 Regulation of Apoptosis by Bcl-2 Family Proteins -- 4.4.1 Derepression Model -- 4.4.2 Direct-Activation Model -- 4.4.3 Embedded Together Model -- 4.4.4 Unified Model -- 4.4.5 Unresolved Issues in the Regulation of Apoptosis -- 4.5 Targeting Bcl-2 Family for Cancer Therapy -- 4.5.1 Targeting Anti-apoptotic Proteins -- 4.5.1.1 Pan-Bcl-2 Inhibitors -- 4.5.1.2 Bcl-2 Selective Inhibitors -- ABT-737/263/199: Targeting Bcl-XL/Bcl-2 -- Specifically Targeting Mcl-1 -- A Novel Path to Screen Selective and Active Bcl-2 Inhibitors -- 4.5.2 Targeting the Pore-Forming Pro-apoptotic Proteins -- 4.6 The Clinical Implications of Bcl-2 Localization at the Endoplasmic Reticulum -- 4.7 Targeting Bcl-2 Family in Other Diseases -- 4.8 Epilogue -- References -- Chapter 5: IAP Proteins and Their Therapeutic Potential -- 5.1 Inhibitor of Apoptosis Protein Family -- 5.2 Ubiquitin Ligase Activity of IAP Proteins -- 5.3 Regulation of Cell Death Pathways by IAP Proteins. , 5.3.1 Role of IAP Proteins in Apoptotic Pathways -- 5.3.2 Role of IAP Proteins in Necroptosis -- 5.4 IAP Proteins as Critical Modulators of Signaling Pathways -- 5.4.1 Regulation of Canonical NF-κB Signaling by IAP Proteins -- 5.4.2 Regulation of Noncanonical NF-κB Signaling by IAP Proteins -- 5.4.3 Regulation of Other Signaling Pathways by IAP Proteins -- 5.5 Relevance of IAP Proteins for Human Malignancies -- 5.6 Targeting IAP Proteins for Therapeutic Intervention -- 5.6.1 Mechanism of Action of IAP Antagonist -- 5.6.2 c-IAP and XIAP Selective Antagonists -- 5.6.3 Pro-apoptotic Combinations of IAP Antagonists -- 5.6.4 Clinical Development and Future Perspectives of Targeting IAP Proteins -- References -- Chapter 6: Cell Death and Cancer -- 6.1 Evading Apoptosis Is a Hallmark of Cancer -- 6.1.1 Bcl-2 Is the Archetype of a Novel Class of Oncogenes: Inhibitors of Cell Death -- 6.1.2 The Tumour-Suppressor p53 Promotes Apoptosis -- 6.1.3 IAPs Are Over-Expressed in Many Cancer Types -- 6.1.4 Function of IAPs -- 6.2 Cell Death in Cancer Therapy -- 6.2.1 The Goal of Cancer Therapy Is to Remove or Kill All Malignant Cells -- 6.2.2 Cells Are Complex Systems That Endeavor to Maintain Homeostasis -- 6.2.3 Conventional Cancer Therapies Cause Cell Death Both by Direct Toxicity and by Inducing Cell Suicide -- 6.2.4 Cell Death and Resistance to Chemotherapy -- 6.2.4.1 Novel Treatments That Use Our New Understanding of Physiological Cell Death -- Bcl-2 Inhibitors -- Smac Mimetics -- P53-Activating Drugs -- 6.3 Conclusions -- References -- Chapter 7: The DNA Damage Response Mediates Apoptosis and Tumor Suppression -- 7.1 DNA Damage Induced Cell Death -- 7.2 The DNA Damage Response -- 7.3 Death in the Absence of DNA Damage -- 7.4 DNA-Damage Mediated Apoptosis -- 7.5 p53-Dependendent Pathways of Apoptosis in Response to DNA Damage. , 7.6 The Regulation of p53 Levels in Response to DNA Damage -- 7.7 p53-Independendent Pathways of Apoptosis in Response to DNA Damage -- 7.8 DNA Damage Response and p53-Mediated Apoptosis in the Prevention of Tumorigenesis -- 7.9 DNA Damage Response Promotes p53-Mediated Cell Competition in HSCs and May Promote Tumorigenesis -- 7.10 Concluding Remarks -- References -- Chapter 8: Neuronal Death Mechanisms in Development and Disease -- 8.1 Apoptosis in Developing Neurons -- 8.2 Unique Molecular Features of Apoptosis Regulation in Neurons -- 8.3 Restriction of Apoptosis with Neuronal Maturation -- 8.4 Nonapoptotic Functions of Caspases in Neurons: Neurite Pruning and Synaptic Plasticity -- 8.5 Neuronal Cell Death in Disease and Injury -- References -- Chapter 9: The Complex Interplay Between Metabolism and Apoptosis -- 9.1 Introduction -- 9.2 Brief Overview of Metabolism -- 9.3 Apoptosis and Survival Signaling -- 9.3.1 The Core Apoptotic Machinery -- 9.3.2 Signaling Molecules that Modulate the Core Cell Death Machinery -- 9.4 Interplay Between Metabolism and Apoptosis -- 9.4.1 Pro-apoptotic Proteins -- 9.4.1.1 Caspase-8 -- 9.4.1.2 Caspase-2 -- 9.4.1.3 PUMA -- 9.4.1.4 Noxa -- 9.4.1.5 BAD -- 9.4.1.6 Bid -- 9.4.1.7 Cytochrome c -- 9.4.1.8 p53 -- 9.4.2 Pro-survival Proteins -- 9.4.2.1 Bcl-2 -- 9.4.2.2 Bcl-x L -- 9.4.2.3 Mcl-1 -- 9.4.2.4 PI3K-Akt -- 9.4.2.5 AMPK -- 9.4.2.6 Sirtuins -- 9.5 Metabolism and Apoptosis in Disease -- 9.6 Conclusion -- References -- Chapter 10: Programmed Necrosis/Necroptosis: An Inflammatory Form of Cell Death -- 10.1 Introduction -- 10.2 The Morphology of Necrosis -- 10.3 A Defined Signaling Pathway Regulates Necrosis -- 10.4 Checkpoint 1: Necrosis is Controlled by Protein Ubiquitination -- 10.5 Checkpoint 2: Caspase-8 is a Negative Regulator of Necrosis. , 10.6 Checkpoint 3: Phosphorylation Promotes RHIM- Mediated Necrosome Formation -- 10.7 RHIM-Mediated Amyloidal Fibril Assembly: A Novel Paradigm in Cell Death Signaling -- 10.8 Downstream Regulators of Necrosis -- 10.9 Role of Necrosis in Innate Inflammatory Responses: Viral Infections -- 10.10 Necrosis in Bacterial Infections -- 10.11 Necrosis in Sterile Inflammation -- 10.12 Direct Roles for RIPK1 and RIPK3 in Inflammation Signaling -- 10.13 Necrosis in Lymphocyte Tolerance and Immune Homeostasis -- 10.14 Concluding Remarks -- References -- Chapter 11: Structural Perspectives on BCL-2 Family of Proteins -- 11.1 Introduction -- 11.2 BCL-2 Family of Proteins -- 11.3 Structural Insights of Anti-apoptotic BCL-2 Proteins -- 11.4 Structural Insights of Pro-apoptotic Bax and Bak -- 11.5 Structural Insights of Pro-apoptotic BH3-Only Proteins -- 11.6 Structural Studies of BH3 Domains with Anti-apoptotic BCL-2 Members -- 11.7 Structural Studies of BH3 Domains with Pro-poptotic Bax and Bak -- 11.8 Summary -- References -- Chapter 12: Structural Basis of Death Receptor Signaling -- 12.1 Introduction -- 12.2 Fas- and TNFR1-Induced Apoptosis -- 12.3 Structures of Individual Proteins and Binary Complexes in the DISC and Other DD Fold Signaling Complexes -- 12.4 DD Interactions in the PIDDosome and Myddosome as Principles of Oligomeric Assembly in the DISC -- 12.5 Structure of the Fas DD: FADD DD Complex in the DISC -- 12.6 Implications for Other DD Complexes in Apoptosis- Inducing Complexes -- 12.7 DED Interactions in DISCs -- 12.8 TNFR1-Induced Programmed Necrosis -- 12.9 Structure of the RIP1/RIP3 Complex in Programmed Necrosis -- 12.10 Summary -- References -- Index.