Bunce / Campbell Nuclear Receptors

Current Concepts and Future Challenges
1. Auflage 2010
ISBN: 978-90-481-3303-1
Verlag: Springer Netherlands
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 8, 458 Seiten

Reihe: Proteins and Cell Regulation

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.

Autoren/Hrsg.

Bunce, Chris M.

Campbell, Moray J.

Inhaltsverzeichnis

1;Foreword;6
2;Contents;8
3;List of Contributors;6
4;1 Nuclear Receptors an Introductory Overview;14
4.1;1.1 Receptors Inside Cells ;14
4.1.1;1.1.1. Nuclear Receptors;15
4.2;1.2 Historical Aspects;16
4.2.1;1.2.1. The Early Years;16
4.2.2;1.2.2. Key Concepts Begin to Emerge;17
4.2.2.1;1.2.2.1. Primary structure of nuclear receptors;18
4.2.2.2;1.2.2.2. Different receptor classes bind DNA in differing ways;19
4.2.2.3;1.2.2.3. A unifying nomenclature system;20
4.2.2.4;1.2.2.4. Different receptor classes bind at selective response elements;20
4.2.2.5;1.2.2.5. Nuclear receptors can both trans-activate and trans-repress gene expression via binding to response elements;21
4.3;1.3 Towards A More Integrated View Of Nr Signalling;22
4.4;1.4 Non Genomic Actions Of Nrs;23
4.5;1.5 Here We Go;24
4.6;References;24
5;2 What does Evolution Teach us about Nuclear Receptors?;27
5.1;2.1 Introduction;27
5.2;2.2 Nrs Phylogeny And Classification;28
5.3;2.3 Nr Complexity Is Not Limited To Vertebrates;29
5.4;2.4 Nr-Like Are Found Throughout The Tree Of Life;31
5.5;2.5 What Is A Nr-Ligand?;33
5.6;2.6 Evolution Of Ligand Binding;34
5.7;2.7 Conclusion: Evolution As A Reflection frame to Understand NRs ;37
5.8;References;37
6;3 Functions of Nuclear Receptors in Insect Development;42
6.1;3.1 Introduction;42
6.2;3.2 Nuclear Receptors In Invertebrates;43
6.3;3.3 Insect Nuclear Receptors: The 20-Hydroxyecdysone-Mediated Pathway;44
6.3.1;3.3.1. The Functional 20-Hydroxyecdysone Receptor. EcR (NR1H1) and USP/RXR (NR2B4);47
6.3.2;3.3.2. E75 (NR1D3);50
6.3.3;3.3.3. E78 (NR1E1);52
6.3.4;3.3.4. HR3 (NR1F4);52
6.3.5;3.3.5. HR4 (NR6A6);53
6.3.6;3.3.6. FTZ-F1 (NR5A3);54
6.3.7;3.3.7. HR39 (NR5B1);55
6.4;3.4 Inhibiting The 20E-Signalling Pathway;56
6.4.1;3.4.1. HR78 (NR2D1);56
6.4.2;3.4.2. HR38 (NR4A4);57
6.4.3;3.4.3. Seven-up (NR2F3);57
6.5;3.5 20E-Independent Nuclear Receptors;58
6.5.1;3.5.1. HR96 (NR1J1);58
6.5.2;3.5.2. HNF4 (NR2A4);59
6.5.3;3.5.3. Tailless (NR2E2);60
6.5.4;3.5.4. Dissatisfaction (NR2E4);61
6.5.5;3.5.5. HR51 (NR2E3), HR83 (NR2E5) and NR2E6;61
6.5.6;3.5.6. Estrogen-Related Receptor (NR3B4);62
6.5.7;3.5.7. The NR0 Subfamily;62
6.6; Acknowledgements;63
6.7;References;63
7;4 The Glucocorticoid Receptor;73
7.1;4.1 Introduction;73
7.2;4.2 Classic Gr And Its Signaling Pathway;75
7.2.1;4.2.1. Domain Structure of GR;75
7.2.2;4.2.2. Hormone Binding and Nuclear Translocation;76
7.2.3;4.2.3. GR Signaling by Direct Binding to DNA;78
7.2.4;4.2.4. GR Signaling by Interactions with Other Transcription Factors;79
7.3;4.3 Gr Post-Translational Modifications And Glucocorticoid Signaling;81
7.3.1;4.3.1. Phosphorylation of GR;81
7.3.2;4.3.2. Ubiquitination of GR;82
7.3.3;4.3.3. Sumoylation of GR;83
7.3.4;4.3.4. Acetylation of GR;83
7.4;4.4 Gr Splice Variants And Glucocorticoid Signaling;84
7.4.1;4.4.1. GR Gene and Alternative Processing at 5 End of Primary Transcript ;84
7.4.2;4.4.2. Splice Variant GR;86
7.4.3;4.4.3. Other GR Splice Variants;88
7.5;4.5 Gr Translational Isoforms And Glucocorticoid Signaling;88
7.6;4.6 Conclusion;90
7.7;References;91
8;5 Estrogen Receptors: Their Actions and Functional Roles in Health and Disease;100
8.1;5.1 Introduction And Historical Perspective;100
8.2;5.2 Primary Structure, Isoforms And Polymorphisms Of Er s ;102
8.3;5.3 Functional Domains Of Er And Er;102
8.3.1;5.3.1. The N-Terminal A/B Domain;103
8.3.2;5.3.2. The DNA-Binding C Domain;103
8.3.3;5.3.3. The Hinge (D) Domain;104
8.3.4;5.3.4. The Ligand Binding E Domain;104
8.3.5;5.3.5. The F-Domain;107
8.4;5.4 Ligand-Induced Conformation And Surface Morphology: Effects And Consequences;108
8.5;5.5 Gene Regulation By Er And Er In Response To Ligands;109
8.6;5.6 Rapid Non-Genomic And Membrane-Mediated Mechanisms;112
8.7;5.7 Physiological Importances Of Estrogens;112
8.7.1;5.7.1. Breast Tissue;113
8.7.2;5.7.2. Urogenital Tract;113
8.7.3;5.7.3. Skeletal Homeostasis;114
8.7.4;5.7.4. Metabolic Effects;116
8.7.5;5.7.5. The Cardiovascular System;118
8.7.6;5.7.6. The Central Nervous System and the Hypothalamo-Pituitary Axis;120
8.8;5.8 WomenS Health Initiative And Beyond;121
8.9;5.9 Estrogen Receptors And Cancer;122
8.9.1;5.9.1. Prostate Cancer;122
8.9.2;5.9.2. Breast Cancer;123
8.10;5.10 Development Of Estrogen Receptor Subtype-Selective Ligands;124
8.11;5.11 Concluding Remarks;124
8.12;References;125
9;6 Androgen Receptor;151
9.1;6.1 Introduction;151
9.1.1;6.1.1. Physiologic Roles and Clinical Application of Androgens;152
9.1.2;6.1.2. Gene and Protein Structure and Function;154
9.1.2.1;6.1.2.1. AR gene and protein structure;154
9.1.2.2;6.1.2.2. AR protein conformation and function;155
9.1.2.3;6.1.2.3. Nongenomic actions of androgens;160
9.1.3;6.1.3. Androgen Biochemistry;161
9.1.3.1;6.1.3.1. Testosterone synthesis, metabolism, and tissue disposition;161
9.1.3.2;6.1.3.2. Testosterone modes of action;164
9.2;6.2 Chemistry Of Ar Ligands;165
9.2.1;6.2.1. Steroidal AR Ligands;165
9.2.1.1;6.2.1.1. Chemistry, structure-activity relationship;165
9.2.1.2;6.2.1.2. Clinical applications;167
9.2.2;6.2.2. Nonsteroidal AR Ligands;167
9.2.2.1;6.2.2.1. Chemistry, structure-activity relationship;168
9.2.2.2;6.2.2.2. Antiandrogen withdrawal syndrome;172
9.2.3;6.2.3. Selective Androgen Receptor Modulators (SARMs);172
9.2.3.1;6.2.3.1. Chemistry;173
9.2.3.2;6.2.3.2. Tissue selectivity of SARMs;173
9.2.3.3;6.2.3.3. Mechanisms of tissue selectivity;174
9.3;6.3 Ar Structural Biology;177
9.3.1;6.3.1. Crystal Structures of Steroid-Bound AR LBD;178
9.3.2;6.3.2. Crystal Structures of Nonsteroidal Ligand-Bound AR LBD;179
9.3.2.1;6.3.2.1. Bicalutamide bound AR LBD (W741L);179
9.3.2.2;6.3.2.2. Aryl propionamide bound AR LBD (WT);180
9.3.2.3;6.3.2.3. Hydantoin derivatives bound AR LBD (WT);182
9.3.2.4;6.3.2.4. Quinolone derivatives bound AR LBD (WT);182
9.4;6.4 Future Perspectives;184
9.5;References;185
10;7 Thyroid Hormone Receptors;191
10.1;7.1 Historical Introduction To Thyroid Hormone Receptors;191
10.2;7.2 Production Of Thyroid Hormone: Systemic And Local Control;193
10.3;7.3 Transcriptional Activity Of The Tr;194
10.4;7.4 T3-Dependent And T3-Independent Functions Of The Tr;195
10.5;7.5 The Tr Family;196
10.6;7.6 Differential Expression Of TRs ;197
10.7;7.7 Biological Functions Of TRs ;197
10.8;7.8 Cooperative Functions Of Tr Isoforms;200
10.9;7.9 Disease;201
10.10;7.10 Concluding Remarks;202
10.11;References;202
11;8 The Vitamin D Receptor (NR1I1);210
11.1;8.1 The Vitamin D Receptor;211
11.1.1;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
11.1.2;8.1.2. Homology Within Nuclear Receptor Superfamily;212
11.1.3;8.1.3. The Choreography of Transcriptional Regulation;213
11.1.3.1;8.1.3.1. Generic VDR transcriptional regulation;213
11.1.3.2;8.1.3.2. Signal specificity;214
11.1.4;8.1.4. Vitamin D Response Elements;216
11.2;8.2 Vdr Actions In Normal Tissues;217
11.2.1;8.2.1. Lessons from Murine Models;217
11.2.1.1;8.2.1.1. Calcified tissues;218
11.2.1.2;8.2.1.2. Skin and hair;219
11.2.1.3;8.2.1.3. The reproductive organs;220
11.2.1.4;8.2.1.4. The cardiovascular system;221
11.3;8.3 The Pathobiology Of Vdr;221
11.3.1;8.3.1. Bone Phenotpyes;221
11.3.2;8.3.2. VDR and Cancer;222
11.3.2.1;8.3.2.1. Evidence of VDR involvement in cancer;222
11.3.2.2;8.3.2.2. In vivo studies;224
11.3.2.3;8.3.2.3. The VDR in DNA damage and repair;225
11.3.2.4;8.3.2.4. Therapeutic exploitation;226
11.3.3;8.3.3. Autoimmune Diseases and Graft Rejection;228
11.3.4;8.3.4. Antimicrobial Actions;229
11.3.5;8.3.5. Mechanisms of Disruption;229
11.3.5.1;8.3.5.1. Reduced environmental availability of 10,25(oh) 2 D 3 ;229
11.3.5.2;8.3.5.2. Cellular resistance;230
11.3.5.3;8.3.5.3. Genetic resistance;230
11.3.5.4;8.3.5.4. Epigenetic resistance;231
11.4;8.4 Towards A Unified Understanding Of The Vdr;232
11.5;References;234
12;9 Retinoic Acid Receptors;244
12.1;9.1 Retinoid Receptors;244
12.1.1;9.1.1. Structure of Retinoic Receptors;244
12.1.2;9.1.2. Transcription of Retinoid-Target Genes;246
12.1.3;9.1.3. Regulation of RXR/RAR-Mediated Transcription;248
12.2;9.2 Origin And Roles Of Retinoids;249
12.2.1;9.2.1. Origin, Synthesis and Metabolism of Retinoids;249
12.2.2;9.2.2. Natural and Synthetic Retinoids;249
12.2.3;9.2.3. Roles of Retinoids and Their Receptors;250
12.3;9.3 Retinoid Receptor Alterations In Human Cancers;251
12.3.1;9.3.1. RAR: Molecular Genetics of APL;251
12.3.2;9.3.2. RAR a Tumour Suppressor Gene;253
12.4;9.4 Antimour Activity Of Ra;254
12.4.1;9.4.1. RA and Differentiation Therapy;254
12.4.2;9.4.2. RA and Death Signalling Pathway;256
12.4.3;9.4.3. RA in Chemoprevention;256
12.5;9.5 Conclusion;257
12.6;References;257
13;10 PPARs: Important Regulators in Metabolism and Inflammation;266
13.1;10.1 Introduction;266
13.2;10.2 Ppar (NR1C1);269
13.2.1;10.2.1. Metabolism;270
13.2.1.1;10.2.1.1. Lipid metabolism;270
13.2.1.2;10.2.1.2. Glucose metabolism;271
13.2.1.3;10.2.1.3. Amino acid metabolism;271
13.2.2;10.2.2. Inflammation;271
13.2.2.1;10.2.2.1. Hepatic inflammation;272
13.2.2.2;10.2.2.2. Inflammation in vascular wall;272
13.3;10.3 Ppar/(NR1C2);273
13.3.1;10.3.1. Lipid Metabolism;274
13.3.1.1;10.3.1.1. Lipid metabolism in skeletal muscle;274
13.3.1.2;10.3.1.2. Lipid metabolism in heart;274
13.3.1.3;10.3.1.3. Lipid metabolism in adipose tissue;275
13.3.1.4;10.3.1.4. Lipoprotein metabolism;275
13.3.2;10.3.2. Wound Healing;275
13.3.3;10.3.3. Inflammation;276
13.4;10.4 Ppar (NR1C3);276
13.4.1;10.4.1. Metabolism;277
13.4.1.1;10.4.1.1. Adipose tissue;277
13.4.1.2;10.4.1.2. Non-adipose tissue;278
13.4.2;10.4.2. Inflammation;278
13.4.2.1;10.4.2.1. Atherosclerosis;279
13.4.2.2;10.4.2.2. Adipose tissue;280
13.5;10.5 Concluding Remarks;280
13.6;References;281
14;11 Xenobiotic Receptors CAR and PXR;293
14.1;11.1 Introduction;293
14.2;11.2 Regulation Of Xenobiotic And Endobiotic Metabolism By Car And Pxr;294
14.2.1;11.2.1. CAR and PXR in Xenobiotic Metabolism and Liver Pathophysiology;294
14.2.1.1;11.2.1.1. Induction of ADME genes by CAR;294
14.2.1.2;11.2.1.2. Induction of ADME genes by PXR;295
14.2.1.3;11.2.1.3. CAR and PXR in drug--drug and food--drug interactions;295
14.2.2;11.2.2. CAR and PXR in Endobiotic Metabolism and Liver Pathophysiology;296
14.2.2.1;11.2.2.1. Role of CAR and PXR in protection against bile acid toxicity;296
14.2.2.2;11.2.2.2. Negative crosstalk of CAR with other nuclear receptors;296
14.2.2.3;11.2.2.3. Crosstalk of PXR with other nuclear receptors;297
14.2.3;11.2.3. CAR and PXR in Regulation of ADME Gene Expression and Pathophysiology in Small Intestine;297
14.3;11.3 Regulatory Mechanisms Of The Transcriptional Activities And Gene Expression Of Car And Pxr;298
14.3.1;11.3.1. Regulation of the Transcriptional Activities of CAR and PXR;298
14.3.1.1;11.3.1.1. Regulation of the transcriptional activity of CAR;298
14.3.1.2;11.3.1.2. Regulation of the transcriptional activity of PXR;299
14.3.1.3;11.3.1.3. Importance of expression levels of CAR in determining hepatic basal expression and induction of CAR-target genes;299
14.3.1.4;11.3.1.4. Interaction between CAR and PXR;300
14.3.2;11.3.2. Regulation of CAR and PXR Gene Expression;301
14.4;11.4 Species Difference In Gene Regulation And Function Of Car And Pxr Between Humans And Mice;301
14.5;11.5 Summary;302
14.6;References;303
15;12 FXR;312
15.1;12.1 Introduction;312
15.2;12.2 Fxr Ligands;313
15.3;12.3 Fxr Target Genes And Fxre s ;315
15.4;12.4 Fxr Regulates Diverse Metabolic Pathways And Cell Homeostasis;318
15.5;12.5 Fxr And Different Diseases;320
15.5.1;12.5.1. FXR and Cholestasis;320
15.5.2;12.5.2. FXR and Atherosclerosis;321
15.5.3;12.5.3. FXR and Diabetes;322
15.5.4;12.5.4. FXR and Gallstone Disease;322
15.5.5;12.5.5. FXR and Aging;322
15.5.6;12.5.6. FXR and Liver Regeneration;323
15.5.7;12.5.7. FXR and Hepatocarcinogenesis;323
15.5.8;12.5.8. FXR and Other Cancers;325
15.6;12.6 Concluding Remarks;325
15.7;References;326
16;13 Physiological Functions of TR2 and TR4 Orphan Nuclear Receptor;332
16.1;13.1 Introduction;332
16.2;13.2 Tr4 And Fertility;334
16.2.1;13.2.1. TR4 and Male Fertility;334
16.2.2;13.2.2. TR4 and Female Fertility;334
16.3;13.3 Tr4 And Central Nervous System;335
16.3.1;13.3.1. TR4 and Cerebellar Development;335
16.3.1.1;13.3.1.1. Abnormal cerebellum in the adult TR4 --/-- brain;335
16.3.1.2;13.3.1.2. TR4 and cerebellum development;336
16.3.2;13.3.2. TR4 and Myelination in Mouse Forebrain;336
16.4;13.4 Tr4 In Glucose And Lipid Metabolism And Insulin Sensitivity;337
16.5;13.5 Tr2/4 In Embryonic And Fetal -Globin Gene Repression;338
16.6;13.6 Tr4 And Skeletal Muscle;339
16.7;13.7 Tr4 And Bone;341
16.8;13.8 Concluding Remarks And Future Directions;344
16.9;References;344
17;14 Nuclear Receptors and ATP Dependent Chromatin Remodeling: A Complex Story;349
17.1;14.1 Introduction;349
17.1.1;14.1.1. DNA Methylation;350
17.1.2;14.1.2. Covalent Histone Modifications;351
17.1.3;14.1.3. ATP-Dependent Chromatin Remodeling;351
17.2;14.2 Co-Activators And Co-Repressors;352
17.2.1;14.2.1. SWI/SNF as a Nuclear Receptor Co-regulator;353
17.2.2;14.2.2. ISWI as a Nuclear Receptor Co-regulator;355
17.2.3;14.2.3. NuRD as a Nuclear Receptor Co-repressor;356
17.2.4;14.2.4. INO80;356
17.3;14.3 Current Approaches To Studying Nuclear Receptor Coupled Chromatin Remodeling;357
17.3.1;14.3.1. Biochemical Approaches;357
17.3.2;14.3.2. Genomic Approaches;359
17.4;14.4 Summary;360
17.5;References;361
18;15 Non-Genomic Action of Sex Steroid Hormones;368
18.1;15.1 Introduction;368
18.2;15.2 Identity Of Extra-Nuclear Steroid Receptors And Related Aspects;369
18.3;15.3 Role Of Rapid Steroid Signaling In Reproductive Cells;370
18.3.1;15.3.1. Estradiol Receptor;370
18.3.2;15.3.2. Androgen Receptor;372
18.3.3;15.3.3. Progesterone Receptor;373
18.4;15.4 Role Of Rapid Steroid Signaling In Non-Reproductive Cells;374
18.4.1;15.4.1. Estrogen Receptor;374
18.4.2;15.4.2. Androgen Receptor;375
18.4.3;15.4.3. Progesterone Receptor;376
18.5;15.5 Bidirectional Integration Between Extra-Nuclear And Nuclear Steroid Action;377
18.6;15.6 Reversible Cross Talk Between Growth Factors And Steroid Hormones;378
18.7;References;379
19;16 Ligand Regulation and Nuclear Receptor Action;383
19.1;16.1 Introduction;383
19.2;16.2 Serum Binding Proteins And The Cellular Acquisition Of Nuclear Receptor Ligands;384
19.2.1;16.2.1. Introduction;384
19.2.2;16.2.2. Cellular Acquisition of Receptor Ligands: Free Versus Bound;385
19.2.3;16.2.3. Nuclear Receptor Responses in Serum Binding Protein Knockout Mice;386
19.2.4;16.2.4. Mechanisms for the Transfer of Extracellular Ligands to Intracellular Binding Sites;389
19.3;16.3 Subcellular Trafficking Of Nuclear Receptor Ligands;391
19.3.1;16.3.1. Introduction;391
19.3.2;16.3.2. Intracellular Transport of Vitamin A;391
19.3.3;16.3.3. Intracellular Binding Proteins and the Cytoplasmic Trafficking of Vitamin D and Estrogen;395
19.4;16.4 Pre-Receptor Metabolism Of Nuclear Receptor Ligands;398
19.4.1;16.4.1. Introduction;398
19.4.2;16.4.2. Pre-receptor Activation of Adrenal Steroids;398
19.4.3;16.4.3. Pre-receptor Activation of Dietary/Environmental Ligands;401
19.4.4;16.4.4. Catabolism of Nuclear Receptor Ligands;402
19.4.5;16.4.5. Tissue-Specific Metabolism and the Regulation of Thyroid Receptor Function;406
19.5;16.5 Summary;408
19.6;References;409
20;17 New Insights to Nuclear Receptor Gene Regulation from Analysis of their Response Elements in Target Genes;420
20.1;17.1 Introduction;420
20.2;17.2 The Nr Superfamily;421
20.3;17.3 Nrs As Molecular Switches;422
20.4;17.4 Chromatin;423
20.5;17.5 Nr Res ;424
20.5.1;17.5.1. ChIP Analysis: The Concept of Multiple REs;425
20.6;17.6 Chip-Chip And Chip-Seq Analysis;426
20.7;17.7 Res In The Chromatin Context;428
20.8;17.8 Negative Res ;429
20.9;17.9 Methods For In Silico Screening Of Nr Binding Sites;430
20.10;17.10 The Classifier Method;431
20.11;17.11 Conclusion;432
20.12; Acknowledgments;433
20.13;References;433
21;18 Systems Biology: Towards Realistic and Useful Models of Molecular Networks;439
21.1;18.1 The Shift From Molecular To Systems Biology;439
21.2;18.2 Hierarchical Networks;440
21.3;18.3 From Molecular Interactions And Reactions To Networks;441
21.4;18.4 A Kinetic Model For Transcription Factor Binding To Dna;442
21.5;18.5 Gene Activity;446
21.6;18.6 Network Regulation Of Gene Activity And M rna Level;448
21.7;18.7 Conclusion;450
21.8;References;450
22;Index;454