Apoptosome (eBook)

Cecconi_Frontmatter.pdf 1
Anchor 1 4
Anchor 2 6
Cecconi_Ch01.pdf 9
Chapter 1 9
Physiological and Pathological Role of Apoptosis 9
1.1 Introduction 9
1.2 The Apoptotic Pathways 10
1.2.1 The Extrinsic Pathway 11
1.2.2 The Intrinsic Pathway 11
1.3 Apoptosis in Development 13
1.3.1 Apaf1 Knockout 14
1.3.2 Caspase-9 Knockout 14
1.3.3 Caspase-3 Knockout 15
1.3.4 Cytochrome c Knockout and Knockin 15
1.3.5 Bax Knockout 16
1.3.6 Bcl-2 Knockout 17
1.3.7 Bcl-X Knockout 17
1.4 Apoptosis in Disease: A Life or Death Decision 18
1.4.1 Too Little Apoptosis 19
1.4.1.1 Neoplastic Diseases 19
1.4.1.2 Autoimmune Diseases 20
1.4.1.3 Virus Infections 21
1.4.2 Too Much Apoptosis 22
1.4.2.1 Neurodegenerative Diseases 22
1.4.2.2 Tissue Damage 24
1.4.2.3 HIV-1 Infection 25
References 26
Cecconi_Ch02.pdf 35
Chapter 2 35
Apoptosome Structure and Regulation 35
2.1 Introduction 35
2.2 The Apoptosome 36
2.2.1 Apaf 1 36
2.2.2 Apoptosome Assembly 38
2.2.3 Apoptosome Structure 39
2.2.4 Cytochrome c 40
2.2.5 Apoptosome Dependent Caspase-9 Activation 41
2.2.6 IAPs as Modulators of the Apoptosome 41
2.3 The Apoptosome in Evolution 42
2.3.1 Caenorhabditis elegans 43
2.3.2 Drosophila Melanogaster 44
References 45
Cecconi_Ch03.pdf 48
Chapter 3 48
Chemical Regulation of the Apoptosome: New Alternative Treatments for Cancer 48
3.1 Introduction 49
3.2 The Intrinsic Cell Death Pathway an Evolutionary Conserved Pathway? 52
3.3 Cytochrome c a Protein Signalling Molecule for Apoptosome Formation 53
3.4 Cytochrome c Unlocks Apaf-1 to Initiate Apoptosome Formation 57
3.5 Apoptosome Formation Requires Adenine Nucleotides 60
3.6 The Apoptosome Recruits Caspase-9 to Form a Caspase-Processing Complex 61
3.7 Physiological and Chemical Regulation of Apoptosome Formation 64
3.8 Physiological and Chemical Regulation of Apoptosome Dependent Caspase Activation 68
3.9 Aberrant Apaf-1 Levels and Apoptosome Formation in Cancer 70
3.10 The Apoptosome a Good Target for New Alternative Treatments for Cancer Therapy? 73
References 74
Cecconi_Ch04.pdf 82
Chapter 4 82
Molecules That Bind a Central Protein Component of the Apoptosome, Apaf-1, and Modulate Its Activity 82
4.1 Introduction 82
4.2 Protein-Dependent Regulation of Apaf-1 83
4.2.1 Apo-cytochrome c 84
4.2.2 Interactions with Bcl-2 Family Members 84
4.2.3 Apaf-1 and Heat Shock Proteins Interactions 84
4.2.4 Apaf-1 Interactions with Proteins Implicated in Cell Cycle 85
4.2.5 Proteins Implicated in Ischemic Processes Able to Interact with Apaf-1 86
4.2.6 Apaf-1 Interactions with Phosphatases and Kinases 86
4.2.7 HCA66 – Apaf-1 Interaction 87
4.3 Transcriptional Regulation of Apaf-1 87
4.4 Chemical Regulation of Apaf-1 89
4.4.1 Apaf-1 Inhibitors 89
4.4.1.1 Diarylurea Compounds 89
4.4.1.2 Peptoid Inhibitors 91
4.4.1.3 Taurine 94
4.4.1.4 Intracellular Concentration of Potassium and Calcium 94
4.4.1.5 Nitric Oxide Donors 95
4.4.1.6 dATP/ATP 95
4.4.2 Apaf-1 Activators 95
4.4.2.1 Wells’ Activator 96
4.4.2.2 Deoxyadenosine Analogs 97
4.4.2.3 PETCM 97
4.5 Conclusion 97
References 98
Cecconi_Ch05.pdf 102
Chapter 5 102
Regulation of Cell Death and Survival by RNA Interference – The Roles of miRNA and siRNA 102
5.1 Introduction 102
5.2 Regulation of Gene Expression by RNAi 103
5.2.1 Mechanism: from miRNA to siRNA 103
5.2.2 siRNA Design 105
5.2.3 Delivery of siRNA or shRNA 106
5.2.4 Off-Target Effects 108
5.3 RNAi As a Tool in Apoptosis Research and Its Therapeutic Implications 108
5.3.1 Developmental Apoptotic Cell Death: Lessons from Worms and Flies 109
5.3.2 Cancer 110
5.3.3 Neurodegenerative Diseases 112
5.3.4 Viral Infections 115
5.3.5 Ischemic Cell Death 117
5.4 Outlook 118
References 119
Cecconi_Ch06.pdf 125
Chapter 6 125
Beneficial Role of Taurine Against Myocardial Apoptosis During Ischemic Injury 125
6.1 Introduction 125
6.2 Role of Anti-apoptotic Effect of Taurine Against Myocardial Ischemia 127
6.2.1 Effect of Taurine on Myocardial Ischemic Injury 127
6.2.2 Effect of Taurine on Myocardial Ischemia/Reperfusion Injury 127
6.2.3 Taurine and Calcium Paradox 129
6.3 Signaling Pathway Involved in the Anti-apoptotic Effect of Taurine in the Ischemic Myocardium 129
6.3.1 Mitochondria-Mediated Signaling Pathway 129
6.3.2 caspase-8-Mediated Apoptotic Pathway 130
6.3.3 Akt/Protein Kinase B 131
6.3.4 Protein kinase C isoforms 131
6.4 Potential Actions Related to Anti-apoptotic Effect of Taurine 132
6.4.1 Oxidative Stress and Calcium Overload 132
6.4.2 Osmotic Stress 133
6.5 Conclusion 134
Cited articles 136
Cecconi_Ch07.pdf 142
Chapter 7 142
BAG3 Protein: Role in Some Neoplastic Cell Types and Identification as a Candidate Target for Therapy 142
7.1 Introduction 142
7.2 BAG3 Protein and bag3 Gene 143
7.3 Functional Activity of BAG3 144
7.4 Conclusions 147
References 148
Cecconi_Ch08.pdf 152
Chapter 8 152
Targeting Survivin in Cancer Therapy: Pre-clinical Studies 152
8.1 Introduction 153
8.2 Survivin Structure and Function 154
8.2.1 The Structure of Survivin 154
8.2.2 Functional Roles of Survivin 154
8.2.3 Survivin Splice Variants 156
8.3 Survivin Expression in Normal and Tumor Tissues 156
8.4 Current Understanding of the Role of Survivin in Treatment Resistance 157
8.4.1 Survivin as a Chemoresistance Factor 157
8.4.2 Survivin as a Radioresistance Factor 158
8.5 Therapeutic Targeting of Survivin 158
8.5.1 Molecular Antagonists 159
8.5.1.1 Antisense Oligonucleotides 159
8.5.1.2 Ribozymes 160
8.5.1.3 Small Interfering RNAs 161
8.5.2 Small Molecules 162
8.5.2.1 Cyclin-Dependent Kinase (CDK) Inhibitors 162
8.5.2.2 Hsp90 Inhibitors 162
8.5.2.3 YM155 163
8.5.2.4 Terameprocol 163
8.5.3 Adenoviral Expression of Dominant-Negative Mutants of Survivin 164
8.5.4 Survivin-Based Immunotherapy 164
8.6 Conclusions and Future Directions 165
References 166
Cecconi_Ch09.pdf 174
Chapter 9 174
Hsp70 and Hsp27: Emerging Targets in Cancer Therapy 174
9.1 Introduction 175
9.2 Cytoprotective Functions of Hsp70 and Hsp27 176
9.2.1 Hsp70 and Hsp27 Are Molecular Chaperones 176
9.2.2 Hsp27 and Hsp70 Interfere with the Action of Key Apoptotic Proteins 178
9.2.2.1 Hsps, Cell Signalling and Apoptosis 178
9.2.2.2 Hsp70 180
Hsp70 and Mitochondrial Dependent Apoptosis 180
Hsp70 and the Extrinsic Death Receptor Pathway 181
Hsp70 and Alternatives, Caspase-Independent, Apoptosis-Like pathways 182
In Conclusion, Hsp70 Can Be Considered as the Quintessential Inhibitor of Apoptosis 183
9.2.2.3 Hsp27 184
9.3 Hsps and Cancer 186
9.3.1 Hsp70: Tumorigenicity and Cancer Cell Resistance 186
9.3.2 The Inhibition of Hsp70 in Cancer Therapy 187
9.3.3 Hsp27, Tumorigenicity and Cancer Cell Resistance 188
9.3.4 The Inhibition of Hsp27 in Cancer Therapy 189
9.4 Anti-Cancer Therapeutical Approaches Based on Extracellular Hsps 190
9.4.1 Extracellular Hsps Have an Immunological Function 190
9.4.2 Immuno-therapeutical Approaches Based on Hsps 193
9.5 Concluding Remarks 194
References 195
Cecconi_Ch10.pdf 208
Chapter 10 208
Role of the RNA-Binding Protein HuR in Apoptosis and Apoptosome Function 208
10.1 Introduction 209
10.2 Post-transcriptional Regulation of Gene Expression 210
10.3 HuR 210
10.3.1 HuR and the Stress Response 211
10.3.2 HuR and Apoptosis 211
10.4 Anti-apoptotic HuR Target mRNAs 213
10.4.1 Prothymosin a 213
10.4.2 SIRT1 213
10.4.3 Bcl-2, Mcl-1 214
10.4.4 p21 214
10.4.5 COX-2 215
10.4.6 HIF-1a 215
10.4.7 Cyclins 215
10.4.8 MKP-1 216
10.5 Pro-Apoptotic HuR Target mRNAs 216
10.5.1 p53 216
10.5.2 c-myc 217
10.5.3 p27 217
10.5.4 Cytochrome c 218
10.6 Anti-Apoptotic HuR Protein Partners 218
10.6.1 SETa 218
10.7 Pro-apoptotic HuR Protein Partners 219
10.7.1 PP32/PHAPI 219
10.8 Perspective: HuR as a Master Modulator of Apoptosome Function 220
References 221
Cecconi_Ch11.pdf 226
Chapter 11 226
Acetylcholinesterase as a Pharmacological Target in Cancer Research 226
11.1 Introduction 226
11.2 Regulation of Acetylcholinesterase Gene Expression 227
11.3 Alternative Splicing Variants of Acetylcholinesterase Distribution 227
11.4 Cholinergic Function of Acertylcholinesterase 228
11.5 Non-cholinergic Function of Acertylcholinesterase 228
11.6 Targeting Acertylcholinesterase to Treat Neurodegeneration 229
11.7 Role of Acertylcholinesterase in Apoptosis 230
11.7.1 Involvement of Acetylcholinesterase in Differentiation and Proliferation 230
11.7.2 Involvement of Acetylcholinesterase in Apoptosis 230
11.7.3 Alternative Splicing Variants of Acetylcholinesterase Distribution in Cells Undergoing Apoptosis 231
11.8 Non-hydrolytic Activity of Acertylcholinesterase in Apoptosis 232
11.9 Apoptosome 232
11.10 How Dose Acetylcholinesterase Participate in Apoptosome? 233
11.11 Modulation of Acetylcholinesterase Activity 234
11.12 Conclusion and Future Direction 235
References 236
Cecconi_Ch12.pdf 242
Chapter 12 242
Putative Role of HCA66, A New Apaf-1 Interacting Protein, in the Physiopathology of NF1 Microdeletion Syndrome Patients 242
12.1 Introduction 243
12.2 HCA66, a Novel Regulator of the Apoptosome 244
12.2.1 HCA66 Interacts with Apaf-1 244
12.2.2 A Role for HCA66 in Apoptosis 245
12.2.3 Haploinsufficiency of HCA66 May Causes Apoptosis Defects in Cell Lines Derived from Patients with NF1 Gene Microdeleti 246
12.2.3.1 General Clinical Features of Neurofibromatosis Type 1 248
12.2.3.2 Genetics and Molecular Mechanisms of Neurofibromatosis Type 1 249
12.2.3.3 Other Modifying Genes Involved in Classical Neurofibromatosis Type I and NF1 Microdeletion Syndrome 250
12.2.3.4 HCA66 and NF1: a Possible Connection 251
12.2.3.5 Conclusion and Future Directions 252
References 252
Cecconi_Ch13.pdf 257
Chapter 13 257
Cristae Remodeling and Mitochondrial Fragmentation: A Checkpoint for Cytochrome c Release and Apoptosis? 257
13.1 Introduction 257
13.2 Regulation of Mitochondrial Morphology 259
13.3 Mitochondrial Fragmentation During Apoptosis 262
13.4 The Cristae Remodelling Pathway 263
13.5 The Molecular Mechanisms and Consequences of Mitochondrial Fission During Cell Death 264
13.6 The Molecular Mechanisms of Cristae Remodeling 266
13.7 Can be Cristae Remodeling Targeted in a Proapoptotic Therapy? 268
13.8 Conclusions 268
References 269
Cecconi_Ch14.pdf 275
Chapter 14 275
Apoptosome Pharmacological Manipulation: From Current Developments in the Laboratory to Clinical Implications 275
14.1 Translational Research: Finding a ‘Common Language’ for Clinicians and Scientists 275
14.2 Drug Discovery Process: From Laboratory to Patient 277
14.2.1 Drug Discovery 278
14.2.2 Pre-clinical Testing 278
14.2.3 Clinical Trials 278
14.2.3.1 New Drug Application (NDA) 279
14.3 Antiapoptotic Drug: The Therapeutic Challenge for Neurodegenerative Diseases 279
14.3.1 The Role of Mitochondria in Neurodegeneration 280
References 284
Cecconi_Ch15.pdf 286
Chapter 15 286
The Therapeutic Role of Taurine in Ischaemia-Reperfusion Injury 286
15.1 Taurine and Ischaemia-Reperfusion Injury 286
15.2 Ischaemia-Reperfusion Injury 287
15.3 Biochemistry of Ischaemia-Reperfusion Injury 287
15.3.1 Free Radicals 287
15.3.2 Lipid Peroxidation 289
15.3.3 Therapeutic Implications 289
15.4 Non-Pharmacological Interventions to Attenuate Ischaemia-Reperfusion Injury 290
15.4.1 Cold 290
15.4.2 Preservative Solutions 290
15.4.3 Ischaemic Preconditioning 291
15.5 Pharmacological Approaches to Attenuating Ischaemia-Reperfusion Injury 292
15.5.1 Iron Chelation 292
15.6 Superoxide Dismutase and Catalase 292
15.6.1 Antioxidants Other Than Taurine 294
15.6.2 Vitamin C (Ascorbic Acid) 294
15.6.3 Vitamin E (Alpha-Tocopherol) 295
15.6.4 Lazaroids 295
15.6.5 EPC-K1 296
15.6.6 Transresveratrol 296
15.7 Experimental Evidence for a Role for Taurine in Ischaemia-Reperfusion Injury 296
15.7.1 Cellular Experiments 296
15.7.2 Taurine and Myocardial Ischaemia-Reperfusion Injury 297
15.7.3 Isolated Perfused Heart Models 297
15.7.4 Intact Animals 298
15.7.5 Taurine and Pulmonary Ischaemia-Reperfusion Injury 298
15.7.6 Taurine and Hepatic Ischaemia-Reperfusion Injury 298
15.7.7 Taurine and Renal Ischaemia-Reperfusion Injury 299
15.7.8 Taurine and Retinal Ischaemia-Reperfusion Injury 299
15.7.9 Taurine and Cerebral Ischaemia-Reperfusion Injury 299
15.7.10 Taurine and Gastrointestinal Ischaemia-Reperfusion Injury 300
15.7.11 Taurine and Testicular Ischaemia-Reperfusion Injury 300
15.7.12 Taurine and the Distant Consequences of Ischaemia-Reperfusion Injury 300
15.7.13 Taurine and Skeletal Muscle Ischaemia-Reperfusion Injury 300
15.8 Human Studies 301
15.9 Future Developments 302
References 302
Cecconi_Ch16.pdf 308
Chapter 16 308
Targeting Survivin in Cancer Therapy: Clinical Considerations 308
16.1 Introduction 309
16.2 Cancer Biomarker Targeting Survivin 310
16.2.1 Cancer Diagnostic Marker 310
16.2.2 Prognostic Marker 310
16.2.3 Predictor of the Response to Cancer Treatment 311
16.3 Cancer Therapeutic Strategies Targeting Survivin 312
16.3.1 Inhibition of Survivin mRNA and Protein Expression: YM155 313
16.3.2 Survivin Antisense Oligonucleotides: LY2181308 313
16.3.3 Destabilizing Survivin Protein 314
16.3.3.1 Terameprocol (EM-1421) 314
16.3.3.2 Flavopiridol 315
16.3.4 Immunotherapy 315
16.3.4.1 Peptide Vaccine 315
Survivin Peptide Vaccine 315
Survivin-2B, a Splicing Variant of Survivin, Peptide Vaccine 316
16.3.4.2 Dendritic Cell (DC) Vaccine 319
16.4 Conclusions 320
References 320
Cecconi_Backmatter.pdf 324