Forkhead Transcription Factors (eBook)

Vital Elements in Biology and Medicine

Kenneth Maiese (Herausgeber)

eBook Download: PDF

2010 | 2010
292 Seiten
Springer New York (Verlag)
978-1-4419-1599-3 (ISBN)

Infos

Forkhead Transcription Factors: Vital Elements in Biology and Medicine provides a unique platform for the presentation of novel work and new insights into the vital role that forkhead transcription factors play in multiple systems throughout the body. Leading international authorities provide their knowledge and insights to offer a novel perspective for translational medicine that highlights the role of forkhead genes and proteins that may have the greatest impact for the development of new strategies for a broad array of disorders. Equally important, Forkhead Transcription Factors: Vital Elements in Biology and Medicine clearly sets a precedent for the necessity to understand the diverse and complex nature of forkhead proteins since this family of transcription factors can limit as well as foster disease progression depending upon the cellular environment. The presentation and discussion of innovative studies and especially those that examine previously unexplored pathways that may influence clinical survival and longevity offer an exciting approach to address the potential of forkhead transcription factors for new therapeutic avenues in multiple disciplines.

KENNETH MAIESE is a physicianscientist whose interests focus on the basic and clinical mechanisms that control neuronal and vascular longevity and immune system function. He presently is the Chief of the Division of Cellular and Molecular Cerebral Ischemia and is a Professor in the Departments of Neurology and Anatomy and Cell Biology, the Center for Molecular Medicine and Genetics, the Barbara Ann Karmanos Cancer Institute, and the National Institute of Environmental Health Sciences at Wayne State University School of Medicine.

Dr. Maiese graduated from the University of Pennsylvania Suma cum Laude with Distinction and received his medical degree as a Teagle and Grupe Foundation Scholar from Weill Medical College of Cornell University. He obtained his internship and residency at The New York Hospital-Cornell Medical Center and subsequently completed his clinical and basic science postdoctoral training at Cornell and the National Institute of Aging.

Dr. Maiese has been fortunate to receive recognition with outstanding teaching awards and election to America's Top Physicians and The Best of U.S. Physicians. His investigations are designed to translate basic science into successful therapeutic treatments for conditions such as cancer, metabolic disorders, cardiovascular disease, diabetes, stroke, and Alzheimer's disease. His work has received the distinction of 'High Impact Research and Potential Public Health Benefit' by the National Institutes of Health with continuous funding from sources that include the American Diabetes Association, the American Heart Association, the Bugher Foundation, a Johnson and Johnson Focused Giving Award, and the National Institutes of Health. He chairs national grant committees and is a chartered panel member or consultant for several national and international foundations as well as multiple study sections and special emphasis panels for the National Institutes of Health.

Dr. Maiese serves as the Editor-in-Chief for two international journals as well an Associate Editor or a member of the editorial board for several journals, executive committees, technology transfer panels, and scientific advisory councils. Given the broad applications of his work, Dr. Maiese is frequently honored as the chairperson and/or the plenary speaker for a number of international symposiums in a range of disciplines that include cell biology, neuroscience, vascular biology, cardiac disease, molecular oncology, and renal physiology.

Inhalt

PREFACE 6
ABOUT THE EDITOR... 
8 
PARTICIPANTS 9
Table of Contents 
14 
SECTION I Insights into Immunity ,Infection and Cancer 21
CHAPTER 1 FOXO1, T-Cell Trafficking and Immune Responses 
22 
Abstract 22
Introduction 22
Mechanisms of T-Cell Homing into Lymph Nodes 
22 
FOXO1, L-Selectin and T-Cell Homing 
24 
FOXO1 and T-Cell Proliferation 
26 
New Potential Targets of FOXO1 to Impose T-Cell Fate 
28 
FOXO1, T-Cell Egress and Peripheral Homing 
29 
Conclusion 30
References 32
CHAPTER 2 FOXP3 and Its Role in the Immune System 
36 
Abstract 36
Introduction 36
Structure and Function of FOXP3 
37 
Expression of FOXP3 
38 
Ontogeny and Migration of FOXP3+ Cells 
39 
Mechanisms of Suppression Mediated by FOXP3+ T-Cells 
40 
Role of FOXP3+T-Cellsin Suppression of Diseases 
42 
Functions of FOXP3 in Nonhematopoietic Cells 
43 
Concluding Remarks 
43 
References 43
CHAPTER 3 Molecular Regulation of Cellular Immunity by FOXP3 49
Abstract 49
Introduction 49
Discovery of FOXP3 and Key Structural Features 
50 
Phenotype and Function of FOXP3+ Treg Cells 
51 
Role of FOXP3 in the Development of Treg Cells 
51 
Naturally Occurring versus Induced Treg Cells 51
Reprogramming CD4+T-Cells into Treg Cells by Ectopic Expression of FOXP3 
52 
Role of FOXP3 in Conventional T-Cells 
53 
Molecular and Cellular Biology of IPEX 
53 
Isoforms of FOXP3 in Humans 
54 
FOXP3 Protein Interactions 55
Homo-Oligomerization 55
Interactions with NFAT 55
Interactions with API 55
Interactions with NFKB 56
Interactions with Runx1 56
Interaction with ROR-a 
56 
Interaction with ROR-.t 
56 
The FOXP3-TIP60-HDAC7 Complex 
57 
Interaction with HDAC9 57
Post-Translational Modifications of FOXP3 
57 
Epigenetic Regulation of FOXP3 and Its Target Genes 
58 
Epigenetics of Genes Regulated by FOXP3 
58 
Epigenetic Regulation of FOXP3 Expression 
58 
Role of FOXP3 in Treg versus 1h17 Cell Development 
59 
Conclusion 60
References 60
CHAPTER 4 The Biology of FoxP3: AKey Player in Immune Suppression during Infections, Autoimmune Diseases and Cancer 66
Abstract 66
Introduction 66
The Discovery of FoxP3 
66 
Functional and Structural Features of FoxP3 
67 
Forkhead Domain 
67 
Leucine Zipper Domain 68
Forkhead- Leucine Zipper Linker Region 68
N-Terminal Proline Rich Repressor Domain 
68 
Multiple Isoforms and Subcellular Localization 
69 
FoxP3 Regulation and Function 69
Role of FoxP3 in Developmentand Function of Tregs 
69 
Cell Extrinsic Regulation of FoxP3 
70 
Epigenetic and Posttranslational Regulation of Foxp3 
70 
Role of FoxP3 in Cancer 
71 
FoxP3 in Infectious Diseases 71
Parasitic Infections 71
ViralInfections 72
HIV Infection 
72 
Foxp3 in Transplantation Tolerance 72
FoxP3 in Autoimmune Diseases 73
Multiple Sclerosis 73
Inflammatory Bowel Diseases 
73 
Type I Diabetes 73
Emerging and Potential Therapeutic Intervention 73
References 75
SECTION II Elucidating the Components Responsible for Vascular Development and Disease in the Cardiovascular System 79
CHAPTER 5 The Cooperative Roles of Foxcl and Foxc2 in Cardiovascular Development 80
Abstract 80
Introduction 80
FoxC1 and FoxC2 Proteins 
80 
Overlapping Expression of 
81 
Developmental Defects in Foxc Mutant Mouse Embryos 
81 
Mutations in FOXC1 and FOXC2 Genes Associated with Developmental Disorders in Humans 
82 
Cooperative Roles of Foxc1 and Foxc2 in Cardiovascular Development 
83 
Foxc Function in Arterial Specification 83
Foxc Function in Lymphatic Vessel Development 85
Foxc Function in Angiogenesis 85
Foxc Function in the Second Heart Field 87
Foxc Function in Cardiac Neural Crest Cells 
89 
Foxc Function in Epicardial-Derived Cells 89
Future Directions 90
References 91
CHAPTER 6 FoxO Proteins and Cardiac Pathology 
95 
Abstract 95
The FoxO Family 
95 
The Spectrum of Transcriptional Responses Mediated by FoxO Family Members 
95 
Regulation of FoxO Proteins 
96 
Phosphorylation 96
Ubiquitinization 97
Acetylation 98
Transcriptional Partners of FoxO 
98 
FoxO Transcription Factors in Cardiac Pathology 
99 
Myocardial Ischemia and Post-Ischemic Reperfusion 
99 
Hypertrophy 101
Development 102
Conclusion 102
References 102
CHAPTER 7 The Forkhead Transcription Factors Play Important Roles in Vascular Pathology and Immunology 
107 
Abstract 107
Introduction 107
Introduction of the FOX Transcription Factor Superfamily 
108 
Structure 108
Expression 108
Functional Modes of FOX Transcription Factors 
108 
Combinatorial Regulation of Gene Expression by FOX Transcription Factorsand Other Transcription Factors 109
Post-Translational Modification 
109 
FOX Transcription Factors and Endothelial Cell Pathology 110
Endothelial Apoptosis 110
EPC Apoptosis and Maturation 
111 
Endothelial Cell Proliferation 111
Roles of FOX Transcription Factors in VEGF Signaling 
112 
Endothelial Responses to Stress 
112 
Neovascularization 113
FOX Transcription Factors and Vascular Smooth Muscle Cells (VSMCs) 
113 
VSMC Apoptosis 
113 
VSMC Proliferation 113
FoxO in VSMC Differentiation 
114 
FoxO in Aging VSMCs 114
Roles of Other FOX Transcription Factors in VSMCs 
114 
FOX Transcription Factors, Inflammation and Immune System 115
FOX Transcription Factors and Inflammation 
115 
FoxP3, Regulatory T-Cells and Immune Suppression 
116 
FoxNl and Thymocyte Development 117
FOX Transcription Factorsand T-Cell Activation 
117 
Conclusion 117
References 118
CHAPTER 8 Regulatory T-Cells, FoxP3 and Atherosclerosis 
123 
Abstract 123
Atherosclerosis, Inflammation and Autoimmunity 123
Regulatory T-Cells, Developmental and Functional Aspects 123
FoxP3 in Experimental Models of Autoimmunity and Atherosclerosis 
126 
Foxp3, Regulatory T-Cells and Atherosclerosis in Humans 127
Treg and Atherosclerosis: Prospects 128
References 129
SECTION III Dissecting the Pathways of Neuronal Integration and Plasticity in the Nervous System 132
CHAPTER 9 FOXP Genes, Neural Development, Speech and Language Disorders 133
Abstract 133
Introduction 133
TheFoxp Subfamily 
134 
Discovery of FOXP2 asa 'Language Gene' 
134 
FOXP2 and Specific Language Impairment (SLI) and Autism 135
Expression of Foxp SubfamilyMembers in the Brain 
135 
Basal Ganglia 136
Cerebral Cortex and Hippocampus 
137 
Thalamus 138
Cerebellum 139
Spinal Cord 139
Language Impairments in the Affected Members of the KE Family 
139 
Imaging Studies on the KE Family 139
The FOXP2 Expression Pattern in the Brain and Its Relation to the Cognitive Functions of Speechand Language 139
Phenotype in Foxp2 Mutant Mice 140
Transcriptional Activity of the FOXP2 Protein 
141 
Foxp2 Upstream and Downstream Genes (Fig. 2) 141
Perspectives 142
References 143
CHAPTER 10 Pathophysiological Relevance of Forkhead Transcription Factorsin Brain Ischemia 
146 
Abstract 146
FOXO Phosphorylation Regulating Shuttlingbetween Nucleus and Cytoplasm 
146 
FOXO Phosphorylation in Response to Oxidative and Ischemic Stresses 
148 
Decreased Akt Activity following Brain Ischemia Triggers Activation of Proapoptotic Proteins 
149 
Dephosphorylation and Activation of FOXOs following Brain Ischemia 
149 
Crosstalk between Akt and Calcineurin Signaling in Neuronal Death 
150 
Synergistic Activation of Fas-Ligand Promoter by NFATs and FOXOs 
150 
Downstream Targets for FOXOI in Delayed Neuronal Death 152
Regulation of FOXO Pathways by SIRT1 153
Therapeutic Perspectives 153
References 155
CHAPTER 11 New Insights for FOXO and Cell-Fate Decision in HIV Infection and HIV Associated Neurocognitive Disorder 159
Abstract 159
Introduction 159
FOXO Family Members and General Function 
159 
Regulation of FOXO Protein Activity 
160 
FOXO in HIV-1 Infection and HIV-1 Associated Neurocognitive Disorders 
162 
FOXO in T-Cell Depletion 
163 
Potential Signaling Pathway of FOX03a in T-Cell Depletion 
163 
FOX03a Commits to the Survival o/CentralMemory CD4+ T-Cell in HIV Injection 
164 
FOXO in Macrophage/Monocyte Pathology of HIV-1 Infection 
164 
The Potential Relationship of FOXO Proteins and Viral Replicationin Macrophage 
165 
The DualRole of FOX03a in HIV Infection in Macrophages 
165 
FOXO and HIV-1 Mediated Central Nervous System Damage 
166 
FOXO Proteins in the Regulation of Stem Cell Homeostasis in the Nervous System 
168 
FOXO Proteins Are Pivotal Factors in Neuronal Apoptosis 
169 
FOX03a in Proinflammatory Cytokine-Induced Astrogliosis 
170 
Summary and Future Directions 170
References 171
SECTION IV Translating Vital Cellular Mechanisms into Successful Clinical Care 
176 
CHAPTER 12 FOXP3+ Regulatory T-Cells in Chronic Kidney Disease: Molecular Pathways and Clinical Implications 177
Abstract 177
Introduction 177
Pathobiology of CD4+/FOXP3+ Regulatory T-Cells 
178 
Forkhead BoxP3 and T-Cell Receptor Signalingin Tregs 179
Costimulatory Signaling Pathways and FOXP3 Expression 
179 
Interleukin-2 and FOXP3 Expression 
179 
Impaired CD4+/FOXP3+ Regulatory T-Cell Functionin Patients with ESKD 
180 
Place of oxLDL in Tregs Apoptosis in Patients with ESKD 180
Place of 26S Proteasome in Tregs Apoptosis 180
FOXP3+ Regulatory T-Cells Apoptosis in Uremia: Role of the 26S Proteasome 181
Conclusion 182
References 182
CHAPTER 13 Transcriptional Role of FOXOIinDrug Resistance through AntioxidantDefense Systems 
185 
Abstract 185
Introduction 185
Differential Expression of FOXOl in Cancer Cells 
186 
Induction and Translocation of FOXOl by Paclitaxel in Cancer Cell Lines 186
FOXOI Attenuates Sensitivity to Paclitaxel-Induced Cell Death in Paclitaxel Resistant Cell Lines 189
Attenuation of Oxidative Stress byPaclitaxel and FOXO1 in Ovarian Cancer Cell Lines 190
MnSOD Expression in Paclitaxel Sensitive and Resistant Ovarian Cancer Cell Lines and Ovarian Cancer Samples 
190 
References 193
CHAPTER 14 Foxp3 Expressing Regulatory T-Cells in Allergic Disease 194
Abstract 194
Introduction 194
Background 195
Regulatory T-Cells in Health and Allergic Conditions 196
Health 197
Experimental Models 
197 
Allergic Rhinitis and Asthma 
198 
Mucosal System 199
Atopy 200
Atopic Dermatitis 200
Modulation of TRegs with Treatment 
201 
Glucocorticoids 201
Specific Allergen Immunotherapy 202
Venom Immunotherapy 
203 
Conclusion 204
References 205
CHAPTER 15 Human Clinical Phenotype Associated with FOXN1 Mutations 
209 
Abstract 209
Introduction: Severe Combined Immunodeficiencies 209
The Nude/SCID Phenotype 211
Fox Family Members and Immune System 215
FOXNl Skin Specific Expression and T-Cell Development 
217 
References 218
CHAPTER 16 FOXL2:At the Crossroads of Female Sex Determination and Ovarian Function 221
Abstract 221
Introduction 221
FoxL2 Protein Sequence Is Highly Conserved 222
Expression of FOXL2 
222 
Disease-Causing FOXL2 Mutations in Humans 
223 
Intragenic FOXL2 Mutations 
223 
Missense Mutations 223
Nonsense or Early Stop Codon-Inducing Frameshift Mutations 224
Frameshift Mutations Leading to Elongated Proteins 225
PolyAlanine Length Variations 225
Chromosomal Rearrangement and Extragenic Mutations Leadingto BPES 
225 
A Genotype/Phenotype Correlation? 226
Learning from MiceModels 
226 
Regulation of the Expression and Activity of FOXL2 
227 
Regulation of Target Genes and of Cellular Functions by FOXL2 
231 
FOXL2 Targets in the Pituitary 231
FOXL2 Targets in the Ovary 231
The FOXL2 Response Element (FLRE) and Its Specificity 
235 
Conclusion 236
References 236
CHAPTER 17 FOXO Transcription Factors: From Cell Fate Decisions to Regulation of Human Female Reproduction 241
Abstract 241
Introduction 241
Regulation of FOXO Activity 
242 
FOXO and Cell Fate 
243 
Cell Cycle Progression, Checkpoint Control and Apoptosis 
244 
Cellular Stress Response and Longevity 
245 
Tumor Suppression 
246 
FOXO and the Endometrium 
247 
Endometrial Differentiation and Menstrual Shedding 
247 
The Decidua of Pregnancy 
249 
Endometriosis and Endometrial Cancer 
249 
FOXO and the Ovary 
250 
Follicular Development and Ovulation 
250 
Primary Ovarian Insufficiency 251
References 251
CHAPTER 18 The "O" Class: Crafting Clinical Care with FoxO Transcription Factors 256
Abstract 256
Abbreviations 256
Introduction 257
FoxO Protein Expression 257
FoxO Protein Structure and Function as Transcription Factors 257
FoxO Proteins, Posttranslational Modulation, Novel Signal Transduction Pathways, and Cell Cycle Regulation 
258 
FoxO Proteins, Metabolism and Cell Longevity 262
FoxO Proteins, Stem Cells and Cardiovascular Development 
264 
FoxO Proteins and the Immune System 265
FoxO Proteins and Cancer 266
Conclusions and Future Perspectives for Clinical Care 267
References 268
INDEX 275

Produkt-Details

• Erscheint lt. Verlag: 29.7.2010
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Zusatzinfo: 292 p. 47 illus., 3 illus. in color.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Schlagworte: autoimmune disease • Biology • Development • genes • immune response • immune system • immunity • immunology • Infection • Protein • proteins • Reproduction • termination • transcription • Translation
• ISBN-10: 1-4419-1599-0 / 1441915990
• ISBN-13: 978-1-4419-1599-3 / 9781441915993