Nuclear Receptors (eBook)

Current Concepts and Future Challenges

Chris M. Bunce, Moray J. Campbell (Herausgeber)

eBook Download: PDF

2010 | 2010
XII, 458 Seiten
Springer Netherland (Verlag)
978-90-481-3303-1 (ISBN)

Infos

In 1890 a case of myxedema was treated in Lisbon by the implantation of a sheep thyroid gland with the immediate improvement in the patient's condition. A few years later, medications for the then ill-explained condition of the menopause included tablets made from cow ovaries. In the first quarter of the 20th century the identification of vitamin D, and its sunlight driven production in skin, paved the way to the elimination of rickets as a major medical problem. Twenty years or so later, Sir Vincent Wigglesworth established the endocrine basis of developmental moulting in insects, arguably the most commonly performed animal behaviour on Planet Earth. A paradigm that would unify these disparate observations arose between 1985 and 1987 beginning with the identification of the glucocorticoid receptor and the nuclear receptor super-family. What follows is a timely and positive manifestation of the capacity, productivity and value of international human scientific endeavour. Based on intrigue, lively competition and cooperation a global effort has rapidly fostered a school of biology with widespread ramifications for the understanding of metazoan animals, the human condition and the state of the planet. This book is the first this century to try and capture the spirit of this endeavour, to depict where the field is now and to identify some of the challenges and opportunities for the future.

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In 1980 a case of myxedema was treated in Lisbon by the implantation of a sheep thyroid gland with the immediate improvement in the patient's condition. A few years later, medications for the then ill-explained condition of the menopause included tablets made from cow ovaries. In the first quarter of the 20th century the identification vitamin D3 and its sunlight driven production in skin paved the way to the elimination of rickets as a major medical problem. Twenty years or so later Sir Vincent Wigglesworth established the endocrine basis of developmental moulting in insects, arguably the most commonly performed animal behaviour on Planet Earth. A paradigm that would unify these disparate observations arose between in 1985 and 1987 beginning with the identification of the glucocorticoid receptor and the nuclear receptor super-family. What follows is a timely and positive manifestation of the capacity, productivity and value of international human scientific endeavour. Based on intrigue, lively competition and cooperation a global effort has rapidly fostered a school of biology with widespread ramifications for the understanding of metazoan animals, the human condition and the state of the planet. This book is the first this century to try and capture the spirit of this endeavour, to depict where the field is now and to identify some of the challenges and opportunities for the future.

Inhalt

Foreword 6
Contents 8
List of Contributors 6
1 Nuclear Receptors an Introductory Overview 14
1.1 Receptors Inside Cells 14
1.1.1. Nuclear Receptors 15
1.2 Historical Aspects 16
1.2.1. The Early Years 16
1.2.2. Key Concepts Begin to Emerge 17
1.2.2.1. Primary structure of nuclear receptors 18
1.2.2.2. Different receptor classes bind DNA in differing ways 19
1.2.2.3. A unifying nomenclature system 20
1.2.2.4. Different receptor classes bind at selective response elements 20
1.2.2.5. Nuclear receptors can both trans-activate and trans-repress gene expression via binding to response elements 21
1.3 Towards A More Integrated View Of Nr Signalling 22
1.4 Non Genomic Actions Of Nrs 23
1.5 Here We Go 24
References 24
2 What does Evolution Teach us about Nuclear Receptors? 27
2.1 Introduction 27
2.2 Nrs Phylogeny And Classification 28
2.3 Nr Complexity Is Not Limited To Vertebrates 29
2.4 Nr-Like Are Found Throughout The Tree Of Life 31
2.5 What Is A Nr-Ligand? 33
2.6 Evolution Of Ligand Binding 34
2.7 Conclusion: Evolution As A Reflection frame to Understand NRs 37
References 37
3 Functions of Nuclear Receptors in Insect Development 42
3.1 Introduction 42
3.2 Nuclear Receptors In Invertebrates 43
3.3 Insect Nuclear Receptors: The 20-Hydroxyecdysone-Mediated Pathway 44
3.3.1. The Functional 20-Hydroxyecdysone Receptor. EcR (NR1H1) and USP/RXR (NR2B4) 47
3.3.2. E75 (NR1D3) 50
3.3.3. E78 (NR1E1) 52
3.3.4. HR3 (NR1F4) 52
3.3.5. HR4 (NR6A6) 53
3.3.6. FTZ-F1 (NR5A3) 54
3.3.7. HR39 (NR5B1) 55
3.4 Inhibiting The 20E-Signalling Pathway 56
3.4.1. HR78 (NR2D1) 56
3.4.2. HR38 (NR4A4) 57
3.4.3. Seven-up (NR2F3) 57
3.5 20E-Independent Nuclear Receptors 58
3.5.1. HR96 (NR1J1) 58
3.5.2. HNF4 (NR2A4) 59
3.5.3. Tailless (NR2E2) 60
3.5.4. Dissatisfaction (NR2E4) 61
3.5.5. HR51 (NR2E3), HR83 (NR2E5) and NR2E6 61
3.5.6. Estrogen-Related Receptor (NR3B4) 62
3.5.7. The NR0 Subfamily 62
Acknowledgements 63
References 63
4 The Glucocorticoid Receptor 73
4.1 Introduction 73
4.2 Classic Gr And Its Signaling Pathway 75
4.2.1. Domain Structure of GR 75
4.2.2. Hormone Binding and Nuclear Translocation 76
4.2.3. GR Signaling by Direct Binding to DNA 78
4.2.4. GR Signaling by Interactions with Other Transcription Factors 79
4.3 Gr Post-Translational Modifications And Glucocorticoid Signaling 81
4.3.1. Phosphorylation of GR 81
4.3.2. Ubiquitination of GR 82
4.3.3. Sumoylation of GR 83
4.3.4. Acetylation of GR 83
4.4 Gr Splice Variants And Glucocorticoid Signaling 84
4.4.1. GR Gene and Alternative Processing at 5 End of Primary Transcript 84
4.4.2. Splice Variant GR 86
4.4.3. Other GR Splice Variants 88
4.5 Gr Translational Isoforms And Glucocorticoid Signaling 88
4.6 Conclusion 90
References 91
5 Estrogen Receptors: Their Actions and Functional Roles in Health and Disease 100
5.1 Introduction And Historical Perspective 100
5.2 Primary Structure, Isoforms And Polymorphisms Of Er s 102
5.3 Functional Domains Of Er And Er 102
5.3.1. The N-Terminal A/B Domain 103
5.3.2. The DNA-Binding C Domain 103
5.3.3. The Hinge (D) Domain 104
5.3.4. The Ligand Binding E Domain 104
5.3.5. The F-Domain 107
5.4 Ligand-Induced Conformation And Surface Morphology: Effects And Consequences 108
5.5 Gene Regulation By Er And Er In Response To Ligands 109
5.6 Rapid Non-Genomic And Membrane-Mediated Mechanisms 112
5.7 Physiological Importances Of Estrogens 112
5.7.1. Breast Tissue 113
5.7.2. Urogenital Tract 113
5.7.3. Skeletal Homeostasis 114
5.7.4. Metabolic Effects 116
5.7.5. The Cardiovascular System 118
5.7.6. The Central Nervous System and the Hypothalamo-Pituitary Axis 120
5.8 WomenS Health Initiative And Beyond 121
5.9 Estrogen Receptors And Cancer 122
5.9.1. Prostate Cancer 122
5.9.2. Breast Cancer 123
5.10 Development Of Estrogen Receptor Subtype-Selective Ligands 124
5.11 Concluding Remarks 124
References 125
6 Androgen Receptor 151
6.1 Introduction 151
6.1.1. Physiologic Roles and Clinical Application of Androgens 152
6.1.2. Gene and Protein Structure and Function 154
6.1.2.1. AR gene and protein structure 154
6.1.2.2. AR protein conformation and function 155
6.1.2.3. Nongenomic actions of androgens 160
6.1.3. Androgen Biochemistry 161
6.1.3.1. Testosterone synthesis, metabolism, and tissue disposition 161
6.1.3.2. Testosterone modes of action 164
6.2 Chemistry Of Ar Ligands 165
6.2.1. Steroidal AR Ligands 165
6.2.1.1. Chemistry, structure-activity relationship 165
6.2.1.2. Clinical applications 167
6.2.2. Nonsteroidal AR Ligands 167
6.2.2.1. Chemistry, structure-activity relationship 168
6.2.2.2. Antiandrogen withdrawal syndrome 172
6.2.3. Selective Androgen Receptor Modulators (SARMs) 172
6.2.3.1. Chemistry 173
6.2.3.2. Tissue selectivity of SARMs 173
6.2.3.3. Mechanisms of tissue selectivity 174
6.3 Ar Structural Biology 177
6.3.1. Crystal Structures of Steroid-Bound AR LBD 178
6.3.2. Crystal Structures of Nonsteroidal Ligand-Bound AR LBD 179
6.3.2.1. Bicalutamide bound AR LBD (W741L) 179
6.3.2.2. Aryl propionamide bound AR LBD (WT) 180
6.3.2.3. Hydantoin derivatives bound AR LBD (WT) 182
6.3.2.4. Quinolone derivatives bound AR LBD (WT) 182
6.4 Future Perspectives 184
References 185
7 Thyroid Hormone Receptors 191
7.1 Historical Introduction To Thyroid Hormone Receptors 191
7.2 Production Of Thyroid Hormone: Systemic And Local Control 193
7.3 Transcriptional Activity Of The Tr 194
7.4 T3-Dependent And T3-Independent Functions Of The Tr 195
7.5 The Tr Family 196
7.6 Differential Expression Of TRs 197
7.7 Biological Functions Of TRs 197
7.8 Cooperative Functions Of Tr Isoforms 200
7.9 Disease 201
7.10 Concluding Remarks 202
References 202
8 The Vitamin D Receptor (NR1I1) 210
8.1 The Vitamin D Receptor 211
8.1.1. 1,25(OH) 2 D 3 Synthesis Is Initiated Extremely Effectively in the Skin and Forms Part of an Endocrine Signaling Loop 211
8.1.2. Homology Within Nuclear Receptor Superfamily 212
8.1.3. The Choreography of Transcriptional Regulation 213
8.1.3.1. Generic VDR transcriptional regulation 213
8.1.3.2. Signal specificity 214
8.1.4. Vitamin D Response Elements 216
8.2 Vdr Actions In Normal Tissues 217
8.2.1. Lessons from Murine Models 217
8.2.1.1. Calcified tissues 218
8.2.1.2. Skin and hair 219
8.2.1.3. The reproductive organs 220
8.2.1.4. The cardiovascular system 221
8.3 The Pathobiology Of Vdr 221
8.3.1. Bone Phenotpyes 221
8.3.2. VDR and Cancer 222
8.3.2.1. Evidence of VDR involvement in cancer 222
8.3.2.2. In vivo studies 224
8.3.2.3. The VDR in DNA damage and repair 225
8.3.2.4. Therapeutic exploitation 226
8.3.3. Autoimmune Diseases and Graft Rejection 228
8.3.4. Antimicrobial Actions 229
8.3.5. Mechanisms of Disruption 229
8.3.5.1. Reduced environmental availability of 10,25(oh) 2 D 3 229
8.3.5.2. Cellular resistance 230
8.3.5.3. Genetic resistance 230
8.3.5.4. Epigenetic resistance 231
8.4 Towards A Unified Understanding Of The Vdr 232
References 234
9 Retinoic Acid Receptors 244
9.1 Retinoid Receptors 244
9.1.1. Structure of Retinoic Receptors 244
9.1.2. Transcription of Retinoid-Target Genes 246
9.1.3. Regulation of RXR/RAR-Mediated Transcription 248
9.2 Origin And Roles Of Retinoids 249
9.2.1. Origin, Synthesis and Metabolism of Retinoids 249
9.2.2. Natural and Synthetic Retinoids 249
9.2.3. Roles of Retinoids and Their Receptors 250
9.3 Retinoid Receptor Alterations In Human Cancers 251
9.3.1. RAR: Molecular Genetics of APL 251
9.3.2. RAR a Tumour Suppressor Gene 253
9.4 Antimour Activity Of Ra 254
9.4.1. RA and Differentiation Therapy 254
9.4.2. RA and Death Signalling Pathway 256
9.4.3. RA in Chemoprevention 256
9.5 Conclusion 257
References 257
10 PPARs: Important Regulators in Metabolism and Inflammation 266
10.1 Introduction 266
10.2 Ppar (NR1C1) 269
10.2.1. Metabolism 270
10.2.1.1. Lipid metabolism 270
10.2.1.2. Glucose metabolism 271
10.2.1.3. Amino acid metabolism 271
10.2.2. Inflammation 271
10.2.2.1. Hepatic inflammation 272
10.2.2.2. Inflammation in vascular wall 272
10.3 Ppar/(NR1C2) 273
10.3.1. Lipid Metabolism 274
10.3.1.1. Lipid metabolism in skeletal muscle 274
10.3.1.2. Lipid metabolism in heart 274
10.3.1.3. Lipid metabolism in adipose tissue 275
10.3.1.4. Lipoprotein metabolism 275
10.3.2. Wound Healing 275
10.3.3. Inflammation 276
10.4 Ppar (NR1C3) 276
10.4.1. Metabolism 277
10.4.1.1. Adipose tissue 277
10.4.1.2. Non-adipose tissue 278
10.4.2. Inflammation 278
10.4.2.1. Atherosclerosis 279
10.4.2.2. Adipose tissue 280
10.5 Concluding Remarks 280
References 281
11 Xenobiotic Receptors CAR and PXR 293
11.1 Introduction 293
11.2 Regulation Of Xenobiotic And Endobiotic Metabolism By Car And Pxr 294
11.2.1. CAR and PXR in Xenobiotic Metabolism and Liver Pathophysiology 294
11.2.1.1. Induction of ADME genes by CAR 294
11.2.1.2. Induction of ADME genes by PXR 295
11.2.1.3. CAR and PXR in drug--drug and food--drug interactions 295
11.2.2. CAR and PXR in Endobiotic Metabolism and Liver Pathophysiology 296
11.2.2.1. Role of CAR and PXR in protection against bile acid toxicity 296
11.2.2.2. Negative crosstalk of CAR with other nuclear receptors 296
11.2.2.3. Crosstalk of PXR with other nuclear receptors 297
11.2.3. CAR and PXR in Regulation of ADME Gene Expression and Pathophysiology in Small Intestine 297
11.3 Regulatory Mechanisms Of The Transcriptional Activities And Gene Expression Of Car And Pxr 298
11.3.1. Regulation of the Transcriptional Activities of CAR and PXR 298
11.3.1.1. Regulation of the transcriptional activity of CAR 298
11.3.1.2. Regulation of the transcriptional activity of PXR 299
11.3.1.3. Importance of expression levels of CAR in determining hepatic basal expression and induction of CAR-target genes 299
11.3.1.4. Interaction between CAR and PXR 300
11.3.2. Regulation of CAR and PXR Gene Expression 301
11.4 Species Difference In Gene Regulation And Function Of Car And Pxr Between Humans And Mice 301
11.5 Summary 302
References 303
12 FXR 312
12.1 Introduction 312
12.2 Fxr Ligands 313
12.3 Fxr Target Genes And Fxre s 315
12.4 Fxr Regulates Diverse Metabolic Pathways And Cell Homeostasis 318
12.5 Fxr And Different Diseases 320
12.5.1. FXR and Cholestasis 320
12.5.2. FXR and Atherosclerosis 321
12.5.3. FXR and Diabetes 322
12.5.4. FXR and Gallstone Disease 322
12.5.5. FXR and Aging 322
12.5.6. FXR and Liver Regeneration 323
12.5.7. FXR and Hepatocarcinogenesis 323
12.5.8. FXR and Other Cancers 325
12.6 Concluding Remarks 325
References 326
13 Physiological Functions of TR2 and TR4 Orphan Nuclear Receptor 332
13.1 Introduction 332
13.2 Tr4 And Fertility 334
13.2.1. TR4 and Male Fertility 334
13.2.2. TR4 and Female Fertility 334
13.3 Tr4 And Central Nervous System 335
13.3.1. TR4 and Cerebellar Development 335
13.3.1.1. Abnormal cerebellum in the adult TR4 --/-- brain 335
13.3.1.2. TR4 and cerebellum development 336
13.3.2. TR4 and Myelination in Mouse Forebrain 336
13.4 Tr4 In Glucose And Lipid Metabolism And Insulin Sensitivity 337
13.5 Tr2/4 In Embryonic And Fetal -Globin Gene Repression 338
13.6 Tr4 And Skeletal Muscle 339
13.7 Tr4 And Bone 341
13.8 Concluding Remarks And Future Directions 344
References 344
14 Nuclear Receptors and ATP Dependent Chromatin Remodeling: A Complex Story 349
14.1 Introduction 349
14.1.1. DNA Methylation 350
14.1.2. Covalent Histone Modifications 351
14.1.3. ATP-Dependent Chromatin Remodeling 351
14.2 Co-Activators And Co-Repressors 352
14.2.1. SWI/SNF as a Nuclear Receptor Co-regulator 353
14.2.2. ISWI as a Nuclear Receptor Co-regulator 355
14.2.3. NuRD as a Nuclear Receptor Co-repressor 356
14.2.4. INO80 356
14.3 Current Approaches To Studying Nuclear Receptor Coupled Chromatin Remodeling 357
14.3.1. Biochemical Approaches 357
14.3.2. Genomic Approaches 359
14.4 Summary 360
References 361
15 Non-Genomic Action of Sex Steroid Hormones 368
15.1 Introduction 368
15.2 Identity Of Extra-Nuclear Steroid Receptors And Related Aspects 369
15.3 Role Of Rapid Steroid Signaling In Reproductive Cells 370
15.3.1. Estradiol Receptor 370
15.3.2. Androgen Receptor 372
15.3.3. Progesterone Receptor 373
15.4 Role Of Rapid Steroid Signaling In Non-Reproductive Cells 374
15.4.1. Estrogen Receptor 374
15.4.2. Androgen Receptor 375
15.4.3. Progesterone Receptor 376
15.5 Bidirectional Integration Between Extra-Nuclear And Nuclear Steroid Action 377
15.6 Reversible Cross Talk Between Growth Factors And Steroid Hormones 378
References 379
16 Ligand Regulation and Nuclear Receptor Action 383
16.1 Introduction 383
16.2 Serum Binding Proteins And The Cellular Acquisition Of Nuclear Receptor Ligands 384
16.2.1. Introduction 384
16.2.2. Cellular Acquisition of Receptor Ligands: Free Versus Bound 385
16.2.3. Nuclear Receptor Responses in Serum Binding Protein Knockout Mice 386
16.2.4. Mechanisms for the Transfer of Extracellular Ligands to Intracellular Binding Sites 389
16.3 Subcellular Trafficking Of Nuclear Receptor Ligands 391
16.3.1. Introduction 391
16.3.2. Intracellular Transport of Vitamin A 391
16.3.3. Intracellular Binding Proteins and the Cytoplasmic Trafficking of Vitamin D and Estrogen 395
16.4 Pre-Receptor Metabolism Of Nuclear Receptor Ligands 398
16.4.1. Introduction 398
16.4.2. Pre-receptor Activation of Adrenal Steroids 398
16.4.3. Pre-receptor Activation of Dietary/Environmental Ligands 401
16.4.4. Catabolism of Nuclear Receptor Ligands 402
16.4.5. Tissue-Specific Metabolism and the Regulation of Thyroid Receptor Function 406
16.5 Summary 408
References 409
17 New Insights to Nuclear Receptor Gene Regulation from Analysis of their Response Elements in Target Genes 420
17.1 Introduction 420
17.2 The Nr Superfamily 421
17.3 Nrs As Molecular Switches 422
17.4 Chromatin 423
17.5 Nr Res 424
17.5.1. ChIP Analysis: The Concept of Multiple REs 425
17.6 Chip-Chip And Chip-Seq Analysis 426
17.7 Res In The Chromatin Context 428
17.8 Negative Res 429
17.9 Methods For In Silico Screening Of Nr Binding Sites 430
17.10 The Classifier Method 431
17.11 Conclusion 432
Acknowledgments 433
References 433
18 Systems Biology: Towards Realistic and Useful Models of Molecular Networks 439
18.1 The Shift From Molecular To Systems Biology 439
18.2 Hierarchical Networks 440
18.3 From Molecular Interactions And Reactions To Networks 441
18.4 A Kinetic Model For Transcription Factor Binding To Dna 442
18.5 Gene Activity 446
18.6 Network Regulation Of Gene Activity And M rna Level 448
18.7 Conclusion 450
References 450
Index 454

Produkt-Details

• Erscheint lt. Verlag: 11.3.2010
• Reihe/Serie: Proteins and Cell Regulation
• Reihe/Serie: Proteins and Cell Regulation
• Zusatzinfo: XII, 458 p.
• Verlagsort: Dordrecht
• Sprache: englisch
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizin / Pharmazie ► Studium
• Themenwelt: Naturwissenschaften ► Biologie ► Zellbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Themenwelt: Technik
• Schlagworte: ATP • Development • Estrogen Receptor • Glucocorticoid • hormone receptors • Metabolism • Metazoa • Nuclear receptors • Regulation • thyroid hormone • Vitamin D
• ISBN-10: 90-481-3303-3 / 9048133033
• ISBN-13: 978-90-481-3303-1 / 9789048133031