Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and up-to-date, this book offers a valuable guide to these cellular processes whilst inciting researchers to explore their potentially important connections. Volume 7 provides coverage of the latest developments in autophagosome biogenesis and regulation; the role of autophagy in protein quality control; and the role of autophagy in apoptosis. Attention is given to autophagy in the cardiovascular system, with particular insights into the role of autophagy in atherosclerosis and the distinctive behavior of autophagy in the sinoatrial node. Cutting-edge findings in the relationships between autophagy and lifestyle are explored with the regulation of macroautophagy in response to exercise, as well as the promotion of carcinogenesis via autophagy in response to cigarette smoking. Volume 7 highlights the importance of understanding the role of autophagy in context, as the complexity of autophagic function becomes increasingly clear. Autophagy may be differentially regulated, and may perform distinctive cell-specific functions even within a single tissue. The overall significance of autophagy thus cannot be oversimplified, and must be explored with granular detail of the specific role, function, and area of impact.This book is an asset to newcomers as a concise overview of the complex significance of autophagy, while serving as an excellent reference for more experienced scientists and clinicians looking to update their knowledge. Volumes in the Series
Front Cover 1
Autophagy 4
Copyright Page 5
Dedication 6
Mitophagy and Biogenesis 8
Autophagy and Cancer 12
Some Thoughts on Autophagy and Immunity 14
Autophagy: Friend or Foe? 16
Contents 18
Foreword by Roberta A. Gottlieb 22
Foreword by Eeva-Liisa Eskelinen 24
Preface 26
Contributors 30
Abbreviations and Glossary 34
Autophagy: Volume 1 – Contributions 44
Autophagy: Volume 2 – Contributions 46
Autophagy: Volume 3 – Contributions 48
Autophagy: Volume 4 – Contributions 50
Autophagy: Volume 5 – Contributions 52
Autophagy: Volume 6 – Contributions 54
1 Introduction to Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 7 56
Introduction 57
Specific Functions of Autophagy (A Summary) 59
Autophagy in Normal Mammalian Cells 59
Endoplasmic Reticulum Stress and Autophagy 60
Major Types of Autophagies 62
Macroautophagy (Autophagy) 62
Microautophagy 62
Chaperone-Mediated Autophagy 62
Autophagosome Formation 63
Autophagic Lysosome Reformation 64
Autophagic Proteins 65
Abnormal Proteins 66
Protein Degradation Systems 67
Beclin 1 68
Non-Autophagic Functions of Autophagy-Related Proteins 68
Microtubule-Associated Protein Light Chain 3 69
Monitoring Autophagy 70
Reactive Oxygen Species (ROS) 70
Mammalian Target of Rapamycin (mTOR) 71
Role of Autophagy in Tumorigenesis and Cancer 72
Role of Autophagy in Immunity 74
Autophagy and Senescence 75
Role of Autophagy in Viral Defense and Replication 76
Role of Autophagy in Intracellular Bacterial Infection 77
Role of Autophagy in Heart Disease 78
Role of Autophagy in Neurodegenerative Diseases 79
Cross-Talk between Autophagy and Apoptosis 81
Autophagy and Ubiquitination 84
Aggresome: Ubiquitin Proteasome and Autophagy Systems 85
Autophagy and Necroptosis 86
Mitochondrial Fusion and Fission 86
Selective Autophagies 87
Allophagy 88
Axonophagy (Neuronal Autophagy) 89
Crinophagy 90
Exophagy 90
Glycophagy 91
Lipophagy 92
Role of Lipophagy in Alcohol-Induced Liver Disease 93
Mitophagy 94
Nucleophagy 95
Pexophagy 96
Reticulophagy 97
Ribophagy 98
Xenophagy 99
Zymophagy 99
References 100
I. Autophagosome Biogenesis and Regulation 110
2 Role of Endoplasmic Reticulum in the Formation of Phagophores/Autophagosomes: Three-Dimensional Morphology 112
Introduction 113
The Autophagic Pathway 113
Why is the Phagophore so Elusive? 113
Origin of the Phagophore Membrane 114
Capturing Phagophore Biogenesis Using Electron Microscopy and Electron Tomography 115
Electron Tomography Reveals Connections between the Phagophore and the ER 116
A Note on Sample Preparation for Electron Tomography 119
Methodology for Chemical and Cryofixation of Cells 120
Electron Tomography 121
Concluding Remarks 121
Acknowledgments 122
References 122
3 The Nucleus-Vacuole Junction in Saccharomyces cerevisiae 124
Introduction 125
Structure of the Nucleus-Vacuole Junction 126
Functions of the Nucleus-Vacuole Junction 126
Piecemeal Microautophagy of the Nucleus 127
Role of Nucleus-Vacuole Junctions in Lipid Metabolism 129
Similar Functions in Mammals 130
Conclusion and Perspectives 130
References 131
4 Human WIPIs as Phosphoinositide Effectors at the Nascent Autophagosome: A Robust Tool to Assess Macroautophagy by ... 134
Introduction 135
The Process of Autophagy 135
Yeast Atg18, Atg21, Hsv2 136
Yeast Atg18 and Atg2 Interact and Form a Complex at the PAS 136
Human WIPIs 137
WIPIs and Cancer 138
WIPIs and Canonical Autophagy 138
WIPIs and Noncanonical Autophagy 140
WIPIs and Selective Autophagy 140
WIPIs at Autophagosomal Membranes: Imaging Techniques for the Assessment of Autophagy 140
Acknowledgments 142
References 142
5 Induction of Autophagy: Role of Endoplasmic Reticulum Stress and Unfolded Protein Response 146
Introduction 147
Molecular Machinery of Autophagy 148
The Unfolded Protein Response 149
Initiation and Regulation of Autophagy by UPR Signaling 150
PERK 152
ATF6 152
IRE1 153
Autophagy/UPR in Disease 153
Conclusions 154
References 154
6 Atg16L1 Protein Regulates Hormone Secretion Independent of Autophagy 158
Introduction 159
Atg16L1 Localizes on Dense-Core Vesicles in PC12 Cells Independent of Canonical Autophagy 160
Localization of Atg16L1 in the Neurites of PC12 Cells Independent of Canonical Autophagy 160
Association of Atg16L1 with Dense-Core Vesicles in PC12 Cells 160
Rab33A Recruits the Atg16L1–5–12 Complex to Dense-Core Vesicles in PC12 Cells 161
Specific Interaction Between Rab33A and Atg16L1 in PC12 Cells 161
Rab33A-Dependent Recruitment of Atg16L1 to Dense-Core Vesicles in PC12 Cells 162
Atg16L1 Regulates Hormone Secretion from PC12 Cells Independent of Canonical Autophagy 162
Regulation of Hormone Secretion by Atg16L1 Independent of Canonical Autophagy 162
Involvement of Atg16L1 in a Late Step of Hormone Secretion 164
Discussion 164
Acknowledgments 167
References 167
II. Autophagy in Protein Quality Control 170
7 Macroautophagy of Aggregation-Prone Proteins in Neurodegenerative Disease 172
Introduction 173
Protein Misfolding and the Ubiquitin–Proteasome System 174
Aggregate Formation 175
Macroautophagy 177
Selective Autophagy 178
Aggrephagy 178
Macroautophagy of Aggregation-Prone Proteins in Neurodegenerative Disease 179
Polyglutamine-Expanded Proteins 180
Alpha-Synuclein 182
Tau 183
Amyloid-beta 183
Prion 184
TDP-43 185
SOD1 186
Dynamics and Localization of Aggregates 186
Regulation and Dysregulation of Macroautophagy in Neurodegeneration 187
Macroautophagic Upregulation as a Therapeutic Strategy 188
Concluding Remarks 189
Acknowledgments 190
References 190
8 Lithium Ameliorates Motor Disturbance by Enhancing Autophagy in Tauopathy Model Mice 194
Introduction 195
Lithium Enhances Autophagy in Various Neurodegenerative Diseases 195
Autophagy and Tau 196
Lithium Attenuates Motor Disturbance in Tauopathy Model Mice by Promoting Autophagy 196
Behavioral Analysis 196
Biochemical Analysis 197
Immunohistochemistry of LC3 198
Discussion 200
References 202
9 Beta-Asarone Reduces Autophagy in a Dose-Dependent Manner and Interferes with Beclin 1 Function 204
Introduction 205
Beta-Asarone 205
Beta-Asarone Preparation 205
Distribution of Beta-Asarone in Brain 206
Pharmacokinetics of Beta-Asarone in Rabbits and Rats 206
Transformation and Excretion of Beta-Asarone in Rabbits 206
Pharmacological Effects of Beta-Asarone on the CNS 207
Effects of Beta-Asarone on Beclin 1 Dependent Autophagy 207
Beta-Asarone Reduces Autophagy in a Dose-Dependent Manner 207
Beta-Asarone Interferes with Beclin 1 Function 208
Discussion 209
Acknowledgments 211
References 211
III. Autophagy and Apoptosis 214
10 Apoptosis and Autophagy: The Yin–Yang of Homeostasis in Cell Death in Cancer 216
Introduction 217
Apoptosis (The Yin) 217
Autophagy (The Yang) 219
p53 in Apoptosis and Autophagy 224
The Bcl-2 Family Members in Apoptosis and Autophagy 226
Atg Proteins in Autophagy and Apoptosis 228
p62 in Apoptosis and Autophagy 228
The Lysosome in Apoptosis and Autophagy 229
PUMA in Apoptosis and Autophagy 231
Inhibitors of Apoptosis 231
Acknowledgments 232
References 233
11 Role of Autophagy and Apoptosis in Odontogenesis 238
Introduction 239
Apoptosis in Odontogenesis 239
Apoptosis Distribution in Odontogenesis 240
Roles of Apoptosis in Odontogenesis 240
Autophagy in Odontogenesis 240
Autophagy Distribution in Early Tooth Development 241
Autophagy Distribution in Late Tooth Development 242
Roles of Autophagy in Odontogenesis 243
Connection Between Autophagy and Apoptosis in Odontogenesis 243
Co-Localization of LC3 and TUNEL Signal 243
Ultrastructure Co-Localization of Autophagy with Apoptosis 244
Co-Localization of Beclin 1, Autophagy, and Apoptosis 245
Conclusion 246
Acknowledgments 247
References 247
12 Autophagy Is Required During Monocyte–Macrophage Differentiation 250
Introduction 251
Autophagy Regulates Cell Survival and Cell Death 251
Autophagy and Cell Differentiation 252
The Differentiation of Monocytes into Macrophages 253
The Role of Autophagy During Monocyte-Macrophage Differentiation 254
Autophagy is Induced During Monocyte-Macrophage Differentiation 254
Autophagy is Required for Monocyte-Macrophage Differentiation 255
Inhibition of Autophagy Suppresses GM-CSF-Induced Monocyte Survival 256
JNK Activation is Required for the Disassociation of Beclin 1 and Bcl-2 256
The Cleavage of Atg5 is Blocked During Monocyte Differentiation 257
Discussion 258
Acknowledgments 260
References 260
IV. Autophagy in the Cardiovascular System 262
13 Degradation of HSPGs Enhances LOX-1-mediated Autophagy 264
Introduction 265
LOX-1 and Reactive Oxygen Species 265
Function of LOX-1 and Its Signaling 265
ROS and LOX-1 266
HSPG and Its Function 267
Autophagy 269
HSPG Degradation in Relation to LOX-1-Mediated Autophagy 270
Conclusion 272
References 272
14 The Presence of LC3 and LAMP1 Is Greater in Normal Sino-Atrial Nodal Cells Than in Ordinary Cardiomyocytes, Indicating a ... 274
Introduction 275
Autophagy in Ordinary Cardiac Myocytes 276
Autophagy in the Myocardium under Physiological Conditions 276
Stress-Induced Autophagy in the Myocardium 276
Autophagy in Sino-Atrial Nodal Cells 277
Autophagosomes in SA Nodal Cells 277
Immunodetection of LC3 in SA Node 277
Immunodetection of LAMP1 in SA Node 278
Discussion 279
Acknowledgments 280
References 280
V. Lifestyle and Autophagy 282
15 Regulation of (Macro)-Autophagy in Response to Exercise 284
Introduction 285
Autophagy in Response to Acute Endurance Exercise 286
Signaling Pathways Implicated in Autophagy Activation by Acute Exercise 289
Autophagy in Response to Exercise Training 292
Regulation of Autophagy by Exercise Training in Pathophysiological Conditions 294
Obesity and Diabetes 294
Aging and Sarcopenia 295
Dystrophies and Atrophy 295
Conclusion 296
References 297
16 Cigarette Smoke Promotes Cancer via Autophagy 300
Introduction 301
Cigarette Smoke and Tumor Growth 302
Autophagic Tumor Stroma Model in Cigarette Smoke Treated Fibroblasts 302
Cigarette Smoke Extract Induces Senescence in Fibroblasts through DNA Damage 302
Cigarette Smoke Extract Increases Autophagy and Alters Metabolism in Fibroblasts 304
Cigarette Smoke Extract-Treated Fibroblasts Promote Tumor Growth 305
Discussion 306
Acknowledgments 307
References 307
Index 310
Preface
M.A. Hayat
Autophagy possesses mechanisms that maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Regarding cell survival, tumor cells themselves activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance. Tumors are often subjected to metabolic stress due to insufficient vascularization. Under these circumstances, autophagy is induced and localized to these hypoxic regions, where it supports survival of tumors. Aggressive tumors have increased metabolic demands because of their rapid proliferation and growth. Thus, such tumors show augmented dependency on autophagy for their survival.
This is the seventh volume of the multivolume series, Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. This series discusses in detail almost all aspects of the autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy.
Chapter 1 is a review of many aspects of autophagy, including the topic of selective autophagy (allophagy, axonophagy, crinophagy, exophagy, glycophagy, lipophagy, mitophagy, pexophagy, reticulophagy, xenophagy, and zymophagy). Additional chapters cover molecular mechanisms underlying the initiation of canonical autophagy and phagophore biogenesis. This volume provides a detailed discussion of the factor Atg16L1, essential for canonical autophagy in all eukaryotes. Cells deficient in Atg16L1 exhibit complete loss of autophagosome formation and capacity for bulk degradation. This factor forms a complex with Atg12-conjugated Atg5 and promotes elongation of isolation membranes by recruiting LC3 and by facilitating its lipidation. This volume also presents current knowledge of autophagy initiation with special attention to the phagophore, the small c-shaped double membrane cisterna which arises de novo and is the vital precursor of autophagosome, endosome, and lysosome structures. Electron microscopy shows that the phagophore membrane makes contact with membranes originating from the endoplasmic reticulum (ER) via thin membrane bridges, revealing the role of the ER in phagophore biogenesis. The roles of the human WD-repeat protein interacting with the phosphoinositides (WIPI) family, Beclin 1, Atg14L, and VPS15 are discussed in several chapters, along with discussion of how these factors can be employed to measure autophagy.
Several chapters address the role of autophagy in protein quality control mechanisms, notably the response to ER stress, and the clearance of aggregated proteins in neurodegenerative diseases. The endoplasmic reticulum is a major cellular organelle consisting of a vast reticular network spanning from the nuclear envelope to the plasma membrane. It plays a major role in various cellular processes including protein synthesis and glycosylation, the secretory pathway, and membrane biogenesis. Loss of ER luminal homeostasis, known as ER stress, elicits a cellular response characterized by the activation of a transcriptional program termed the unfolded protein response (UPR), regulated by the ER-located stress sensors IRE1, ATF6, and PERK. The UPR upregulates components of the autophagic machinery and increases autophagic flux. A common feature of neurodegenerative diseases is the accumulation of aggregated proteins, and clearance of such aggregates may be a means to counter neuronal dysfunction. Macroautophagy (autophagy) is implicated in the clearance of such aggregation-prone proteins, and evidence is presented that autophagy is compromised in neurodegenerative disease states. This volume also covers pharmacological interventions such as lithium to upregulate autophagy in neurodegenerative disease. Lithium upregulates the clearance of misfolded proteins, such as α-synuclein, tau, and prion protein. Hyperphosphorylated tau is internalized into LC3-positive autophagosomes. Limitations of this approach are also discussed. Beta-asarone (a plant extract) has the advantage of passing through the blood-brain barrier (BBB) and entering into the brain. It is also known that beta-asarone attenuates neuronal autophagy by interfering with Beclin 1 function in a dose-dependent manner. The possible use of this agent in the treatment of neuronal diseases is discussed in this volume.
This volume elaborates on the cross-talk between autophagy and apoptosis. Autophagy and apoptosis are essential processes for tissue and organ homeostasis, and an imbalance is linked to various diseases. Autophagy and apoptosis are not mutually exclusive pathways. They can collaborate to bring about the death of the cell, but in other settings, autophagy opposes programmed cell death. Many regulators affect both pathways, such as Beclin 1 and Bcl-2, although stressors may elicit different responses from autophagy and apoptosis machinery. Multiple roles played by lysosomes in autophagy and apoptosis are explained. An interesting example of the precise balance of apoptosis and autophagy presented in this volume involves tissue homeostasis throughout tooth development. Autophagic markers (Beclin 1 and LC3) are positively expressed during the entire process of odontogenesis. Because autophagy is involved not only in cell survival but also in cell death, and apoptosis leads only to cell death, an understanding of the critical balance between these two types of cellular processes is required to design anticancer therapeutics.
The impact of lifestyle on autophagy and the (patho) physiological consequences are explained in this volume, using endurance exercise and cigarette smoking as examples. Endurance exercise activates homeostatic mechanisms, including autophagy, to eliminate damaged and misfolded proteins. Autophagy induced by exercise leads to remodeling of muscle fibers and mobilization of muscle proteins as alternate energy substrates for neoglucogenesis by the liver during nutrient limited stress. Exercise increases autophagy at the post-translational level in an insulin/mTOR/ULK1-dependent manner.
It is well-established that cigarette smoking is directly responsible for several types of human cancers. The carcinogens in smoke give rise to DNA mutations in epithelial cells, and recent work reveals that autophagy and mitophagy are induced by exposure to cigarette smoke. As a result of mitophagy, oxidative phosphorylation is diminished, resulting in high levels of lactate and ketones in the cell media and a shift toward glycolytic metabolism. It is concluded that cigarette smoke can promote cancer growth by inducing autophagy in the tumor microenvironment.
The role of autophagy in the heart is examined in this volume. In the heart, basal autophagy is modest under physiological conditions, but increases when the myocardium is exposed to certain stresses, such as ischemia/reperfusion. The basal level of autophagy in sinoatrial (SA) nodal cells is higher than that in ventricular or atrial myocytes. The SA nodal cells contain significantly more autophagosomes than are seen in ordinary myocytes. That these vesicular structures are autophagosomes is confirmed by the upregulation of autophagosome marker LC3 and lysosomal proteins, suggesting a constitutively high level of autophagy is required for SA nodal cell function.
Degradation of heparan sulfate proteoglycans (HSPGs) increases endothelial permeability to atherogenic lipoproteins (LDL), leading to smooth muscle cell proliferation, generation of reactive oxygen species, and upregulation of autophagy. This volume delineates the link between lectin-like oxidized LDL receptor 1 activation, HSPGs, and autophagy.
The intriguing role of autophagy in differentiation of monocytes into macrophages is discussed in this volume. In the absence of stimulation some monocytes are programmed to undergo apoptosis. Stimulation promotes monocyte differentiation to macrophages through a process requiring autophagy. It is explained here that the differentiation signal releases Beclin 1 from Bcl-2 by activating JNK and blocks Atg5 cleavage, both of which are critical for the induction of autophagy. The differentiation signal prevents cleavage of Atg5 into a proapoptotic fragment and permits its participation in autophagy. Simultaneously, the signal activates JNK, which stimulates the dissociation of Beclin 1 from Bcl-2, allowing Bcl-2 to oppose apoptosis and permitting Beclin 1 to activate autophagy. These essential autophagy proteins play a dual role, switching the cell from apoptosis to autophagy and differentiation.
By bringing together a large number of experts (oncologists, physicians, medical research scientists, and pathologists) in the field of autophagy, it is my hope that substantial progress will be made against the terrible diseases that afflict humans. It would be nigh impossible for a single author to cover the current state of knowledge of this exceedingly complex process of autophagy. The participation of multiple authors allows for the presentation of different points of view on controversial aspects of the role of autophagy in health and disease.
This volume was written by 49 contributors representing eight countries. I am grateful to them for their promptness in accepting my suggestions. Their practical experience highlights the very high quality of their writings, which should build and further the endeavors of the readers in this important medical field. I respect and appreciate the hard work and exceptional insight into the...
| Erscheint lt. Verlag | 12.2.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Dermatologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Histologie / Embryologie | |
| Studium ► 2. Studienabschnitt (Klinik) ► Pathologie | |
| Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| Technik | |
| ISBN-10 | 0-12-801052-5 / 0128010525 |
| ISBN-13 | 978-0-12-801052-5 / 9780128010525 |
| Haben Sie eine Frage zum Produkt? |
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