Cellular Senescence and Tumor Suppression (eBook)

Contents 5
Contributors 7
Introduction 10
Section 1 Senescence Signals 13
Telomere Biology and Biochemistry 14
1.1 Introduction 15
1.2 Telomere Structure 18
1.3 Proteins Associated with the Telomeric DNA 20
1.4 Senescence 26
1.4.1 ATM and ATR 27
1.4.2 Other Modulators of a DDR at the Telomere 28
1.5 Telomerase Structure and Function 29
1.6 TERT-associated Proteins 34
1.6.1 Dyskerin 34
1.6.2 Ever Shorter Telomeres (EST)1A/SMG6 36
1.7 Epigenetics at the Telomere 37
1.8 Alternative Lengthening of the Telomere 40
1.9 Conclusions 42
References 43
Role of RecQ Helicases in Nuclear DNA Repair and Telomere Maintenance 55
2.1 Introduction 56
2.2 Telomere: Structure and Maintenance 56
2.3 RecQ Helicases in DNA Repair 59
2.3.1 WRN and BLM in DNA Repair 60
2.3.2 Other Helicases in DNA Repair 62
2.4 RecQ Helicases in Telomere Maintenance 64
2.4.1 Replication 65
2.4.2 Recombination 66
2.4.3 Repair of Oxidative Damage 67
2.5 Perspective 67
References 68
Oncogene-Induced Senescence (OIS) as a Cellular Response to Oncogenic Stresses 73
3.1 Introduction 74
3.2 p53 and the DNA Damage Response Regulate Senescence 77
3.3 Rb Regulates Senescence 78
3.4 Different Senescence Requirements in Human and Mice 80
3.5 Cytokines and Oncogene-Induced Senescence 82
3.6 Senescence, Oncogenes, and Cellular Stresses 83
3.6.1 Oxidative Stress 83
3.6.2 DNA Replication Stress 84
3.6.3 Endoplasmic Reticulum (ER) Stress 84
3.7 Therapeutic Options 85
References 86
Stress-Induced Senescence 94
4.1 Overview: Stresses that Cause Cells to Enter Senescence 94
4.2 Linking DNA Damage and Stress-Induced Senescence: Cyclin- Dependent Kinase Inhibitors p21 and p16 96
4.3 Significance of Stress-Induced Senescence for Tissue Function 98
4.4 Potential Role of Stress-Induced Kinase, p38 MAP Kinase, in Stress- Induced Senescence 99
4.4.1 Upstream Activation of p38 MAP Kinase 103
4.4.2 Generation of ROS and Effects of Antioxidants 103
4.4.3 Disruption of Chromatin Structure as a Potential Mediator of Stress- Induced Senescence 104
4.4.4 Bmi1 and Other Polycomb Proteins 105
4.4.5 Ets1 and Related Transcription Factors 106
4.4.6 p16 mRNA Stabilization 107
4.5 Permanence of Stress-Induced Senescence 107
4.6 Telomerase and Stress-Induced Senescence 108
4.7 Summary 109
References 110
Section 2 The Senescent Phenotype 116
The Secretome of Senescent Cells 117
5.1 Cell Senescence Blocks Cancer 117
5.2 Senescent Cells Regulate Their “Secretome” 119
5.3 Mechanism of Regulation of the Secretome 120
5.4 Impact of the Secretome on Tumor Suppression 122
References 126
Chromatin Structure in Senescent Cells 132
6.1 Annotation of Chromatin Remodelers and Their Function in Aging 132
6.1.1 Introduction to the Histone Code 133
6.1.2 Chromatin Compartments 151
6.2 Early Studies Identified Patches of Dense Chromatin and Heterochromatization in Aged Cells 152
6.3 Everything Old Becomes New Again: The RB-Regulated Heterochromatization Pathway 153
6.4 The Prominent Role of HDAC1 in Senescence and Tissue Aging 156
6.4.1 The Role of HDAC1 in Senescence of Melanocytes and Oncogene- Induced Senescence of Melanocytic Nevi 157
6.4.2 The Opposite Roles of HDAC1 in Young and Old Livers: Guilt by Associations 158
6.5 The Role of Sirtuins in Chromatin Structure of Cells 160
6.6 Conclusions 162
References 166
A Comparison of Senescence in Mouse and Human Cells 182
7.1 General Features of Senescence in Human and Mouse 182
7.2 The Role of Telomeres in Human and Mouse Senescence 183
7.2.1 “Replicative” Senescence of Mouse Cells is Caused by Oxidative Stress 184
7.2.2 Mouse Cells Display Telomere-mediated Senescence in Specific Circumstances 185
7.2.3 Genomic Instability in Mouse and Human Cultured Cells 186
7.3 Other Triggers of Senescence 187
7.4 Pathways Activating Senescence 187
7.4.1 Coevolution of Replicative Senescence and Body Size in Rodents, The Role of Cancer Selection 191
7.4.2 Telomere Biology Across Mammalian Species 194
7.4.3 Summary: Coevolution of Replicative Senescence and Body Mass 196
References 198
Section 3 The Physiological Consequences of Senescence 205
Replicative Senescence as an Intrinsic Tumor- Suppressor Mechanism 206
8.1 Telomere Attrition and Replicative Senescence 207
8.2 Telomere Structure and Function 208
8.3 Telomere Dysfunction, p53 and Cellular Senescence 209
8.4 Telomere Dysfunction Promotes Genomic Instability 211
8.5 Consequences of Telomerase Loss In vivo: The Telomerase Knockout Mouse 212
8.6 Telomere Dysfunction Accelerates Tumorigenesis in the Absence of p53 213
8.7 Telomere Dysfunction Inhibits Tumorigenesis in the Setting of Functional p53 214
8.8 Dysfunctional Telomeres Activate a p53-dependent Senescence Program to Suppress Tumorigenesis 215
8.9 Conclusions and Future Directions 218
References 219
Telomere Dysfunction and Senescence in Stem Cell and Tissues Aging 223
9.1 Introduction 223
9.2 Telomere Dysfunction, Tissue Aging, and Regeneration 224
9.3 Induction of DNA Damage Checkpoints and Senescence During Organismal Aging 226
9.4 Telomere Shortening and Stem Cell Aging 228
9.5 Telomere Dysfunction Induces Cell Intrinsic Checkpoints Limiting Maintenance and Function of Adult Stem Cells 229
9.6 Telomere Dysfunction Induces Cell Extrinsic Alterations Limiting the Function and Engraftment of Adult Stem Cells 233
9.7 Summary and Outlook 234
References 234
Mining Cellular Senescence for Drug Targets 238
10.1 Introduction 239
10.2 Routes to Cell Death 240
10.2.1 Apoptosis 241
10.2.2 Autophagy 244
10.3 Cellular Senescence 246
10.3.1 Replicative Senescence 247
10.3.2 Accelerated Senescence 251
10.4 Targeting Senescence 254
10.4.1 Molecular Regulation of Senescence 254
10.4.2 High Throughput Screening: Trends and Impact 256
10.5 Phenotypic Screening Based on Senescence Markers 257
10.6 Conclusions 259
References 260
Index 269