Apoptosis : physiology and pathology

Title......Page 4
Copyright......Page 5
Contents......Page 6
Contributors......Page 10
1.1. Apoptosis and limited proteolysis......Page 16
1.2. Caspase evolution......Page 17
2.2. The activation platforms......Page 18
2.3. Executioner caspases– activation by cleavage......Page 19
4. REGULATION BY NATURAL INHIBITORS......Page 20
REFERENCES......Page 22
1. THE BIR DOMAIN DEFINES MEMBERSHIP IN THE IAP FAMILY......Page 26
2. CELLULAR FUNCTIONS AND PHENOTYPES OF IAP......Page 28
3. IN VIVO FUNCTIONS OF IAP FAMILY PROTEINS......Page 29
5. IAP AS CASPASE INHIBITORS......Page 30
7. IAP AND SIGNAL TRANSDUCTION......Page 31
8. IAP–IAP INTERACTIONS......Page 32
10. ENDOGENOUS ANTAGONISTS OF IAP......Page 33
11. IAPs AND DISEASE......Page 35
SUGGESTED READINGS......Page 36
1. INTRODUCTION......Page 38
2.1.1. CD95 and CD95L: discovery of the first direct apoptosis-inducing receptor-ligand system......Page 40
2.1.2. Biochemistry of CD95 apoptosis signaling......Page 41
2.2. The TRAIL (Apo2L)\nsystem......Page 42
3.1.1. Biochemistry of TNF signal transduction......Page 45
3.1.2. TNF and TNF blockers in the clinic......Page 46
3.2. The DR3 system......Page 48
5. FUNCTIONAL SPECIALIZATION BY SEQUENTIAL SIGNALING COMPLEX FORMATION IN DEATH RECEPTOR SIGNAL TRANSDUCTION......Page 49
6. CONCLUDING REMARKS AND OUTLOOK......Page 50
SUGGESTED READINGS......Page 51
2. MITOCHONDRIAL PHYSIOLOGY......Page 52
6. DOWNSTREAM OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION......Page 53
8. COMPARISON OF THE VERTEBRATE AND INVERTEBRATE PATHWAYS OF MITOCHONDRIAL CELL DEATH......Page 56
SUGGESTED READINGS......Page 58
2. ACTIVATING APOPTOSIS: BAX AND BAK AND THE ACTIVATOR BH3-ONLY PROTEINS......Page 59
3. INHIBITING APOPTOSIS......Page 61
5. ACTIVATING THE ACTIVATORS – CONNECTING THE INSULT TO THE BCL-2 FAMILY......Page 62
6. THE BCL-2 FAMILY AND CANCER......Page 63
SUGGESTED READINGS......Page 65
2. THE ESR IN YEAST......Page 66
3. THE ESR IN MAMMALS......Page 68
4. THE ESR AND CELL DEATH......Page 72
5. THE ESR IN DEVELOPMENT AND TISSUE HOMEOSTASIS......Page 74
6. THE ESR IN HUMAN DISEASE......Page 75
7. CONCLUSION......Page 77
2. AUTOPHAGY......Page 78
2.1. Molecular dissection of autophagy......Page 79
2.2. Physiologic functions of autophagy......Page 80
2.3. Autophagy and human pathology......Page 81
3.1. Autophagy as anti–cell death mechanism......Page 82
3.2. Autophagy as a cell death mechanism......Page 84
4. AUTOPHAGY, CELLULAR DEATH, AND CANCER......Page 85
SUGGESTED READINGS......Page 87
1. TYPES OF DNA DAMAGE AND REPAIR SYSTEMS......Page 89
2. DNA DAMAGE RESPONSE......Page 90
2.2. Transducers......Page 91
4. CHROMATIN MODIFICATIONS......Page 92
5. CELL CYCLE CHECKPOINT REGULATION......Page 93
6.1. DNA damage response and the induction of apoptosis......Page 94
6.2. p53-independent mechanisms of apoptosis......Page 95
6.3. DNA damage response and senescence induction......Page 96
SUGGESTED READINGS......Page 97
1. INTRODUCTION......Page 103
2. SPHINGOLIPID METABOLISM: CONSTITUENTS, COMPARTMENTALIZATION, AND KEY CONCEPTS......Page 104
3. SPHINGOLIPIDS AS MEDIATORS OF APOPTOTIC SIGNALING......Page 106
3.2. Sphingolipids are cell-signaling molecules......Page 107
3.2.3. Inhibition of ceramide production alters cell death signaling......Page 108
4.1. Ceramide is generated through SM hydrolysis......Page 109
4.2. aSMase is activated after activation of extracellular receptors to promote apoptosis......Page 110
4.4. Controversial aspects of the role of aSMase in apoptosis......Page 111
4.5. De novo ceramide synthesis regulates programmed cell death......Page 112
4.7. The role and regulation of de novo synthesis in ceramide-mediated cell death is poorly understood......Page 114
5. CONCLUDING REMARKS AND FUTURE DIRECTIONS......Page 115
5.3. Where? (Which compartment?)......Page 116
5.6. What purpose?......Page 118
SUGGESTED READINGS......Page 119
2. CYTOTOXIC GRANULES AND GRANULE EXOCYTOSIS......Page 121
2.2. The immunological synapse......Page 122
2.4. Uptake of proapoptotic proteins into the target cell......Page 123
3.1. Perforin......Page 124
3.2. Granulysin......Page 126
3.3.1. GrB-mediated apoptosis......Page 127
3.3.3. Orphan granzyme-mediated cell death......Page 128
4. A ROLE FOR GRANULE PROTEINS IN VIRAL RESPONSE, IMMUNE SURVEILLANCE, AND IMMUNE HOMEOSTASIS......Page 129
5. CONCLUSIONS......Page 130
REFERENCES......Page 131
1.1. Death by trophic factor deprivation......Page 138
1.2.1. Roles of caspases and Apaf-1 in neuronal cell death......Page 139
1.2.2. Role of Bcl-2 family members in neuronal cell death......Page 141
1.3.1. Signals for survival......Page 142
2.1.1. Alzheimers disease......Page 143
2.1.2. Parkinsons disease......Page 144
2.1.4. Amyotrophic lateral sclerosis......Page 145
2.2.1. Calpains......Page 146
SUGGESTED READINGS......Page 147
2. MECHANISTIC TAXONOMY OF CELL DEATH: HOW MANY TYPES OF PROGRAMMED CELL DEATH CAN BE DISTINGUISHED?......Page 150
3. PROGRAMMED CELL DEATH SIGNALING IN NEURODEGENERATION......Page 151
4. APOPTOSIS INDUCED BY MISFOLDED, UNFOLDED, OR ALTERNATIVELY FOLDED PROTEINS......Page 152
5. TROPHIC FACTORS AND CELLULAR DEPENDENCE IN NEURODEGENERATIVE DISEASE......Page 154
SUGGESTED READINGS......Page 156
1. INTRODUCTION......Page 160
3. NMDA RECEPTOR-MEDIATED GLUTAMATERGIC SIGNALING PATHWAYS INDUCE Ca2+ INFLUX AND GENERATION OF RNS/ROS......Page 161
5. S-NITROSYLATION OF PARKIN......Page 162
6. S-NITROSYLATION OF PDI MEDIATES PROTEIN MISFOLDING AND NEUROTOXICITY IN CELL MODELS OF PD OR AD......Page 163
7. POTENTIAL TREATMENT OF EXCESSIVE NMDA-INDUCED Ca2+ INFLUX AND FREE RADICAL GENERATION......Page 164
8. FUTURE THERAPEUTICS: NITROMEMANTINES......Page 165
SUGGESTED READINGS......Page 166
1. CELL DEATH AFTER CEREBRAL ISCHEMIA AND REPERFUSION......Page 168
3. MITOCHONDRIAL PERMEABILITY TRANSITION ACTIVATED BY Ca2+ AND OXIDATIVE STRESS......Page 169
4.2. Bcl-2 family proteins......Page 171
4.4. Caspase-independent apoptosis......Page 175
4.5. Calpains in ischemic neural cell death......Page 176
5. SUMMARY......Page 177
SUGGESTED READINGS......Page 178
2. HISTORICAL ANTECEDENTS......Page 179
3. CELL DEATH IN THE ACUTE PHASE OF SCI: BEYOND THE APOPTOSIS AND NECROSIS DICHOTOMY......Page 180
4. INTRINSIC MEDIATORS OF ACUTE CELL DEATH: EXCITOTOXICITY VERSUS HIF OR JUN......Page 182
5. EXECUTIONER CASPASES IN THE ACUTE PHASE OF SPINAL CORD INJURY......Page 183
6. MITOCHONDRIA AS A TARGET OF SPINAL CORD PROTECTION......Page 184
7. SUBACUTE PHASE: EXTRINSIC PATHWAYS TO DEATH IN NEURONS AND OLIGODENDROCYTES......Page 185
7.1. Activation of p21 waf1/cip1: Targeting extrinsic and intrinsic pathways to death......Page 186
REFERENCES......Page 187
1.1. Lens......Page 191
2.1. Glaucoma......Page 192
2.2. Age-related macular degeneration......Page 193
4. APOPTOSIS AND OCULAR IMMUNE PRIVILEGE......Page 194
SUGGESTED READINGS......Page 195
1. HAIR CELLS ARE THE SENSORY RECEPTOR CELLS IN THE HEARING AND BALANCE ORGANS OF THE INNER EAR......Page 197
3. THE COCHLEA IS THE HEARING ORGAN......Page 198
3.2. Aminoglycoside-induced hair cell death......Page 199
3.3. Cisplatin-induced hair cell death......Page 200
4. SPIRAL GANGLION NEURON DEATH......Page 201
4.2. Afferent activity from hair cells......Page 202
4.3. Molecular manifestations of spiral ganglion neuron death......Page 203
SUGGESTED READINGS......Page 204
3.1. Olfactory epithelium......Page 209
3.2. Olfactory bulb......Page 212
4. Olfaction in Aging and Neurodegenerative Disease......Page 213
REFERENCES......Page 214
2. APOPTOSIS IN PHYSIOLOGIC CONTROL OF BETA CELL MASS......Page 216
3.1. Beta cell death in the development of T1D......Page 217
3.2.1. Apoptosis signaling pathways downstream of death receptors and inflammatory cytokines......Page 218
3.2.2. Oxidative stress......Page 220
3.3.1. Glucolipitoxicity......Page 221
3.3.2. Endoplasmic reticulum stress......Page 223
4. BETA CELL APOPTOSIS AND ISLET TRANSPLANTATION THERAPY......Page 224
REFERENCES......Page 226
2.1. Apoptosis in pulmonary inflammation......Page 236
2.2. Apoptosis in acute lung injury......Page 237
2.4. Apoptosis in interstitial lung diseases......Page 238
2.6. Apoptosis in lung cancer......Page 239
SUGGESTED READINGS......Page 241
2. ESOPHAGUS......Page 278
3. STOMACH......Page 279
4. SMALL AND LARGE INTESTINE......Page 280
5. LIVER......Page 283
6. PANCREAS......Page 284
SUGGESTED READINGS......Page 285
2. APOPTOSIS IN KIDNEY DEVELOPMENT AND CONGENITAL KIDNEY DISEASES......Page 287
3. APOPTOSIS IN ADULT KIDNEY DISEASE......Page 288
4.1. Survival factors......Page 290
4.2.1. TNF superfamily cytokines......Page 291
4.2.4. Drugs and xenobiotics......Page 292
5. THERAPEUTIC APPROACHES......Page 294
SUGGESTED READINGS......Page 295
2.1. Occurrence and role of apoptosis in the developing breast......Page 297
Molecular regulation ofapoptosis in the normal breast......Page 298
2.2.1. Autocrine/paracrine regulation by growth factors, death ligands, and other cytokines......Page 299
2.2.3. TGF3 proapoptotic pathway......Page 300
2.2.5. IGF survival signaling......Page 301
2.2.6. Regulation by adhesion......Page 302
2.2.8. Downstream regulators of apoptosis: the BCL-2 family members......Page 303
3. APOPTOSIS IN BREAST CANCER......Page 304
3.1. Apoptosis in breast tumorigenesis and cancer progression......Page 305
3.2.2. Deregulation of prosurvival growth factors and their receptors......Page 306
3.2.3. Alterations in cell adhesion and resistance to anoikis......Page 307
3.2.5. p53 inactivation in breast cancer......Page 308
3.2.6. Altered expression of BCL-2 family of proteins in breast cancer......Page 309
4. NONAPOPTOTIC TYPES OF CELL DEATH IN NORMAL AND NEOPLASTIC BREAST......Page 310
SUGGESTED READINGS......Page 311
1. INTRODUCTION......Page 320
3. OCCURRENCE AND REGULATION OF CELL DEATH IN THE OVARIES......Page 321
4. APOPTOSIS AND FEMALE REPRODUCTIVE AGING......Page 322
5. ANTIAPOPTOTIC AGENTS AND FERTILITY PRESERVATION FOR CANCER SURVIVORS......Page 324
REFERENCES......Page 325
2. TESTICULAR GERM CELL APOPTOSIS HAS MANY UNIQUE REGULATORY GENES......Page 330
3.1. Murine models......Page 331
3.3. Pathways of caspase activation and apoptosis......Page 332
3.4. Apoptotic signaling in male germ cells......Page 333
4. THE FAS SIGNALING SYSTEM DOES NOT CONTRIBUTE TO HEAT- OR HORMONE DEPRIVATION–INDUCED MALE GERM CELL APOPTOSIS......Page 334
6. P38 MAPK PATHWAY IS ALSO THE KEY PATHWAY FOR HEAT-INDUCED MALE GERM CELL APOPTOSIS......Page 335
7. CASPASE-2 IS AN UPSTREAM ACTIVATOR OF P38 MAPK AND NO-MEDIATED INTRINSIC PATHWAY SIGNALING......Page 337
11. CONCLUSIONS AND PERSPECTIVES......Page 338
REFERENCES......Page 339
2.2. Apoptosis in atherosclerosis......Page 342
2.2.1. Vascular smooth muscle cells......Page 343
2.2.3. Regulation of apoptosis in atherosclerosis......Page 344
3. CELL DEATH IN THE MYOCARDIUM......Page 345
3.1.1. Apoptosis in myocardial infarction......Page 346
3.1.2. Necrosis in myocardial infarction......Page 348
3.2. Cell death in heart failure......Page 349
3.2.1. Apoptosis in heart failure......Page 350
3.2.2. Necrosis in heart failure......Page 351
REFERENCES......Page 352
1.1. Skeletal muscle adaptation to endurance training......Page 360
1.2. Myonuclear domains......Page 362
2. MITOCHONDRIALLY MEDIATED APOPTOSIS IN MUSCLE......Page 363
2.1. Skeletal muscle apoptotic susceptibility......Page 364
3.1. Mitochondrially mediatedapoptosis during chronicmuscle disuse......Page 365
4.1. Aging......Page 366
4.3. Cancer cachexia......Page 367
5. EFFECT OF ENDURANCE EXERCISE/CHRONIC CONTRACTILE ACTIVITY ON APOPTOSIS......Page 368
SUGGESTED READINGS......Page 369
2.1. Cornification and apoptosis......Page 370
2.2. Death receptors in the skin......Page 373
3.1. Sunburn......Page 374
3.2. Skin cancer......Page 376
3.5. Eczema......Page 377
ACKNOWLEDGMENTS......Page 378
SUGGESTED READINGS......Page 379
1. TWO APOPTOTIC PATHWAYS CONVERGE IN CASPASE ACTIVATION......Page 380
2.1. Survival of early hematopoietic progenitors......Page 382
2.2.1. Establishing central tolerance......Page 384
2.2.2. Peripheral tolerance......Page 386
2.3.1. Early B-cell development......Page 388
2.3.3. Survival and death of activated B cells......Page 389
4. CONCLUSIONS......Page 390
REFERENCES......Page 391
1. INTRODUCTION......Page 397
3. HEMATOPOIETIC PROGENITOR EXPANSION AND LINEAGE DETERMINATION......Page 398
4. ERYTHROPOIESIS......Page 399
6. GRANULOPOIESIS......Page 401
7. MONOPOIESIS......Page 403
REFERENCES......Page 404
2. HOST INFLAMMATORY RESPONSE TO SEPSIS......Page 410
3.1. Sepsis-induced apoptosis......Page 411
4. THE DEVELOPMENT OF CLINICALLY RELEVANT ANIMAL MODELS OF SEPSIS......Page 412
4.4. Investigations implicating the intrinsic apoptotic pathway in sepsis......Page 413
5.2. Network effects of selective loss of immune cell types......Page 414
6. DEVELOPING THERAPIES TO AMELIORATE SEPSIS-INDUCED LYMPHOCYTE APOPTOSIS......Page 415
REFERENCES......Page 416
2.1. Commensals versus pathogens......Page 419
2.2. Pathogen strategies to infect the host......Page 420
3.1. Antimicrobial peptides......Page 421
3.2.3. The Nod signalosome......Page 424
3.2.4. The inflammasome......Page 427
3.3.1. Apoptosis and pathogen clearance......Page 429
3.3.2. Pyroptosis......Page 430
4. CONCLUSIONS......Page 432
REFERENCES......Page 433
33 Programmed Cell Death in the Yeast Saccharomyces cerevisiae......Page 436
1. PHENOTYPE AND ASSAYS OF YEAST APOPTOSIS......Page 437
3. EXTERNAL STIMULI THAT INDUCE APOPTOSIS IN YEAST......Page 438
5. PROGRAMMED AND ALTRUISTIC AGING......Page 439
SUGGESTED READINGS......Page 441
2. KILLING......Page 444
3. SPECIFICATION......Page 446
4.2. Mitochondrial elimination......Page 448
4.3. Engulfment......Page 449
SUGGESTED READINGS......Page 450
2. DROSOPHILA CASPASES AND PROXIMAL REGULATORS......Page 454
3. IAP PARTICIPATE IN CASPASE-DEPENDENT CELL DEATH......Page 455
5. DROSOPHILA: WHAT IS UPSTREAM OF THE APOPTOSOME?......Page 456
6. CLOSING COMMENTS......Page 457
SUGGESTED READINGS......Page 458
2.2.1. Studies of gene function using microinjections into early embryos......Page 459
2.3. Forward genetic screening......Page 460
2.5. Transgenesis......Page 461
3.1. Intrinsic apoptosis......Page 462
3.2. Extrinsic apoptosis......Page 463
3.4. Anoikis......Page 464
3.6. Necrosis......Page 465
5. THE P53 PATHWAY......Page 466
SUGGESTED READING......Page 468
Color Plates\r......Page 242