Abbreviations ................................................. xix
List of contributors ........................................ xxiii
1. Why be interested in death? .................................. 1
Nicola J. McCarthy
1. Introduction .............................................. 1
2. Historically speaking ..................................... 1
2.1. Morphological aspects ................................ 2
3. Where does apoptosis occur? ............................... 4
3.1. Primitive death ...................................... 5
4. The importance of regulated cell death .................... 6
4.1. The decision phase ................................... 8
4.2. The commitment phase ................................ 12
4.3. The execution phase ................................. 13
4.4. Summary ............................................. 14
5. Models of apoptosis ...................................... 14
6. Future work .............................................. 16
References .................................................. 16
2. Programmed cell death in C. elegans: the genetic
framework ................................................... 23
DING XUE, YI-CHUN WU, and MANISHA S. SHAH
1. Introduction ............................................. 23
1.1. Advantages of using С. elegans for the study of
programmed cell death ............................... 23
1.2. Origin and identity of dying cells in С. elegans .... 25
1.3. Roles of programmed cell death in С. elegans ........ 25
1.4. Morphology and kinetics of programmed cell death
in С. elegans ....................................... 26
2. Genetic and molecular analysis of programmed cell
death in С elegans ....................................... 27
2.1. The genetic pathway of programmed cell death in C.
elegans ............................................. 27
2.2. Genes involved in the killing process of
programmed cell death ............................... 29
2.3. Genes involved in the specification of the cell
death fate in specific cell types ................... 38
2.4. Genes involved in the engulfment of cell corpses .... 42
2.5. Genes involved in the degradation of cell corpses ... 47
3. Conclusion and future perspectives ....................... 47
Acknowledgements ............................................ 48
References .................................................. 48
3. Genetic and molecular analysis of programmed cell death
in Drosophila ............................................... 56
ANDREAS BERGMANN and HERMANN STELLER
1. Introduction ............................................. 56
2. Description of programmed cell death during Drosophila
development .............................................. 57
3. The H99 cell death genes: reaper, hid, and grim .......... 61
4. Transcriptional regulation of the reaper gene ............ 63
5. The Drosophila gene hid links RAS-dependent cell
survival and apoptosis ................................... 65
6. Drosophila inhibitors of apoptosis (DIAP) ................ 68
7. Drosophila caspases ...................................... 71
8. How do the cell death regulators rpr, hid, and grim
induce cell death in Drosophila? ......................... 74
9. Where are the mammalian rpr/hid/grim homologues? ......... 76
10.Alternative cell death paradigms in Drosophila ........... 77
11.Phagocytosis-the final fate .............................. 79
12.Inhibition of pathological cell death .................... 81
13.Final considerations ..................................... 82
Acknowledgements ............................................ 83
References .................................................. 83
4. The caspases: consequential cleavage ........................ 93
NATALIE ROY and MICHAEL H. CARDONE
1. Introduction ............................................. 93
2. Caspase involvement in apoptosis ......................... 93
3. Class and structure ...................................... 95
3.1. Three-dimensional structure ......................... 95
3.2. Substrate specificity ............................... 98
3.3. Prodomain structure ................................. 98
4. Caspase activation ...................................... 100
4.1. Transactivation .................................... 101
4.2. Aggregation leading to autoprocessing .............. 102
4.3. Caspase activation at the mitochondria ............. 103
4.4. Conformational changes leading to activation ....... 104
5. Caspase inhibition ...................................... 105
6. Caspase substrates ...................................... 108
6.1. Substrate discovery ................................ 108
6.2. Proteolysis regulating function .................... 109
7. Functional diversity .................................... 116
8. Caspases in disease ..................................... 119
9. Conclusion .............................................. 121
References ................................................. 122
5. Regulation of apoptosis by the Bcl-2 family of proteins .... 136
YOSHIHIDE TSUJIMOTO
1. Introduction ............................................ 136
2. Discovery of bcl-2 gene and its anti-apoptotic
activity ................................................ 136
3. Bcl-2 family proteins and regulation of apoptosis ....... 137
4. Biochemical functions ................................... 139
4.1. Role in the mitochondria ........................... 140
4.2. Ion channels formed by the Bcl-2 family proteins ... 143
4.3. Sequestration of caspases by Bcl-2 and Bcl-xL ...... 144
4.4. Role of Bcl-2 localized on the endoplasmic
reticulum and nuclear envelope ..................... 145
5. Regulation of Bcl-2 family proteins ..................... 145
5.1. Regulation of pro-apoptotic members of the Bcl-2
family through post-translational modification ..... 145
5.2. Bcl-2 binding proteins ............................. 147
5.3. Bcl-2 family proteins as a convergence point for
various life-death signals ......................... 148
6. Conclusion .............................................. 148
Acknowledgements ........................................ 148
References .............................................. 149
Addendum: recent discoveries on Bcl-2 family proteins
1. Mechanisms for breaking outer mitochondrial
membrane permeability ................................ 156
2. Protein conducting pores for release of
mitochondrial apoptogenic factors .................... 156
3. ВНЗ-only proteins serve as sensors for various
death signals ........................................ 157
4. Convergence point for life-or-death signals .......... 157
References .............................................. 158
6. Mitochondria in apoptosis: Pandora's Box ................... 161
NAOUFAL ZAMZAMI, SANTOS A. SUSIN, and GUIDO KROEMER
1. Introduction ............................................ 161
2. Mitochondrial contributions to cell death ............... 161
3. Cytochrome с ............................................ 163
4. Mitochondrial caspases .................................. 165
5. Heat shock proteins ..................................... 167
6. Apoptosis-inducing factor (AIF) ......................... 167
7. Additional factors and metabolic changes due to
mitochondrial membrane permeabilization ................. 170
8. Open questions .......................................... 170
References ................................................. 171
7. Apoptosis: lessons from cell-free systems .................. 176
PAUL R. CLARKE
1. Introduction ............................................ 176
2. Studying the biochemistry of apoptosis .................. 177
3. Development of cell-free systems for apoptosis .......... 179
4. Extracts of apoptotic cells ............................. 180
4.1. Investigation of nuclear apoptosis ................. 180
4.2. Identification of apoptotic DNA fragmentation
and chromatin condensation factors ................. 181
4.3. Oncogene-regulated apoptosis ....................... 184
5. Triggering apoptosis in non-apoptotic extracts .......... 184
6. Xenopus egg extracts .................................... 186
6.1. Development of the Xenopus egg extract system ...... 186
6.2. Control of apoptosis in Xenopus egg extracts ....... 188
6.3. Analysis of specific processes in Xenopus egg
extracts ........................................... 193
7. Conclusions ............................................. 193
Acknowledgements ........................................... 194
References ................................................. 194
8. Death signalling by the CD95/TNFR family of death domain
containing receptors ....................................... 200
NICOLA J. MCCARTHY and MARTIN R. BENNETT
1. The death receptor superfamily .......................... 200
1.1. Introduction ....................................... 200
1.2. TNF receptor superfamily ........................... 201
2. Ligands of the TNF receptor superfamily ................. 209
2.1. Introduction ....................................... 209
2.2. Summary ............................................ 211
3. Adaptor proteins ........................................ 212
3.1. FADD, TRADD, and RIP and RIP2 ...................... 212
3.2. Daxx ............................................... 214
3.3. Other CD95/TNF-R1 receptor interacting proteins .... 215
3.4. TRAFs: TNF receptor-associated factors ............. 216
4. Regulation of death receptor-induced killing ............ 217
4.1. The death-inducing signalling complex (DISC) ....... 217
4.2. TNFR signalling pathways ........................... 219
4.3. Summary ............................................ 220
5. Disease states with which death receptor signalling
pathways are associated ................................. 220
5.1. Introduction ....................................... 220
5.2. CD95 and AIDS ...................................... 222
5.3. Cancer ............................................. 223
6. Conclusion .............................................. 224
References ................................................. 224
9. Survival signalling by phosphorylation: PI3K/Akt sets
the stage .................................................. 235
THOMAS F. FRANKE
1. Introduction ............................................ 235
2. Structure of Akt and Akt-related kinases ................ 235
3. Rediscovery of a proto-oncogene ......................... 236
4. Akt as a direct downstream target of PI3K ............... 239
5. PDKl-independent mechanisms of Akt activation ........... 242
6. Negative regulators of PI3K/Akt signalling .............. 242
7. Apoptosis suppression by Akt ............................ 243
8. Protein substrates of Akt ............................... 244
9. Substrate regulation by Akt-dependent phosphorylation ... 246
10.A BAD kinase makes good ................................. 247
11.Other substrates of Akt in apoptosis regulation ......... 248
12.Conclusions ............................................. 249
Acknowledgements ........................................... 251
References ................................................. 251
10.Viruses and apoptosis ...................................... 262
DAVID L. VAUX
1. Introduction ............................................ 262
2. Origins of apoptosis .................................... 262
3. Detection of viruses .................................... 264
4. Viral pro-apoptotic genes? .............................. 264
5. Apoptosis as a defensive response to viral infection .... 265
6. Viral inhibition of apoptosis ........................... 265
6.1. CrmA ............................................... 266
6.2. p35 and IAP ........................................ 267
6.3. FLIPs .............................................. 268
6.4. Anti-p53 ........................................... 269
6.5. Bcl-2 homologues ................................... 269
7. Inhibition of signal transduction pathways involved
in defence .............................................. 270
8. Cytotoxic T cells ....................................... 271
8.1. Viral defence against CTL and other immune system
defences ........................................... 272
9. Conclusions ............................................. 272
References ................................................. 273
11.Cell death in the nervous system ........................... 278
MICHAEL D. JACOBSON and LOUISE BERGERON
1. Cell death in the nervous system ........................ 278
2. Neurotrophins: extracellular survival and death
signals to neurons ...................................... 278
3. Signal transduction ..................................... 279
3.1. Survival signalling ................................ 279
3.2. Death signals ...................................... 283
3.3. Summary: convergence of survival and death
signals ............................................ 287
4. Bcl-2 family and mitochondria ........................... 288
5. Caspases ................................................ 290
6. Neurodegenerative diseases and stroke ................... 290
6.1. Ischaemic stroke ................................... 291
6.2. Polyglutamine repeat diseases ...................... 294
6.3. Alzheimer's disease ................................ 296
6.4. Amyotrophic lateral sclerosis (ALS) ................ 299
6.5. Spinal muscular atrophy (SMA) ...................... 300
7. Conclusions ............................................. 301
References .................................................... 302
Index ......................................................... 317
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