Regulatory Mechanisms in Transcriptional Signaling (eBook)

Debabrata (Debu) Chakravarti (Herausgeber)

eBook Download: EPUB

2009 | 1. Auflage
522 Seiten
Elsevier Science (Verlag)
978-0-08-091198-4 (ISBN)

Infos

Regulatory Mechanisms in Transcriptional Signaling, volume of Progress in Molecular Biology and Translational Science, includes in-depth discussion on
roles of Chromatin remodeling proteins in nuclear receptor signaling, and ANCCA regulator in cancer.

This important resource, edited by Dr. Debabrata (Debu) Chakravarti, offers research on the progesterone receptor action in leiomyoma and endometrial cancer and emerging roles of the ubiquitin protein system in nuclear hormone receptor signaling, in order to provide the reader with expert discussions of up-to-date research.

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Regulatory Mechanisms in Transcriptional Signaling, volume of Progress in Molecular Biology and Translational Science, includes in-depth discussion on roles of Chromatin remodeling proteins in nuclear receptor signaling, and the ANCCA regulator in cancer. This important resource, edited by Dr. Debabrata (Debu) Chakravarti, offers research on the progesterone receptor action in leiomyoma and endometrial cancer and emerging roles of the ubiquitin protein system in nuclear hormone receptor signaling to provide the reader with expert discussions of up-to-date research.

Inhalt

Front Cover 
1 
Progress in Molecular Biology and Translational Science 
4 
Copyright Page 
5 
Contents 
6 
Contributors 
10 
Preface 
12 
References 14
Introduction: Regulatory Mechanisms in Transcriptional Signaling by Nuclear Hormone Receptors, and their Regulators: Implications in Physiology and Disease 
16 
Acknowledgment 
23 
Chapter 1: Regulation of Metabolism by Nuclear Hormone Receptors 
24 
I. Introduction 25
II. The PPARs 27
A. PPARalpha 
27 
B. PPARgamma 28
C. PPARdelta 30
D. PPARs and Atherosclerosis 32
E. PPARs and Inflammation 33
III. LXR 35
A. Regulation of Hepatic Lipid Metabolism by LXR 36
B. Regulation of Reverse Cholesterol Transport by LXR 36
C. LXR and Atherosclerosis 38
D. LXR and Inflammation 38
E. LXR and Diabetes 40
F. Therapeutic Potential of LXR Ligands 41
IV. FXR 42
A. FXR and the Control of Bile Metabolism 43
B. Gallstones, Cholestasis, and Bacterial Growth 44
C. FXR and Lipid Metabolism 45
D. FXR and Atherosclerosis 46
E. FXR and Diabetes 47
F. Control of Liver Regeneration and Tumorigenesis by FXR 47
G. Therapeutic Potential of FXR Ligands 48
V. RORalpha 
49 
A. Regulation of Lipid Metabolism by RORs 49
B. Role of RORs in Circadian Rhythm Control and Links to Metabolism 51
C. RORs and Inflammation 53
D. Therapeutic Potential of RORalpha 
54 
VI. ERRalpha 
54 
A. ERRalpha and the PGC-1alpha Pathway 
55 
B. ERRalpha 
57 
C. ERRalpha 
57 
D. ERRalpha 
58 
E. Therapeutic Potential of ERRalpha Ligands 
59 
VII. Summary 60
References 60
Chapter 2: Progesterone Receptor Action in Leiomyoma and Endometrial Cancer 
76 
I. Introduction 77
II. The Uterus 77
III. Progesterone Action on the Endometrium and Myometrium 79
A. Physiological Response to Progesterone 79
B. Progesterone Receptors 80
C. Coregulators of PR 81
D. Progesterone Receptors in the Endometrium and Myometrium 83
IV. Endometrial Cancer 84
V. Progesterone Receptor Action in Endometrial Cancer 85
A. Progestin Therapy in Women 85
B. Progesterone Receptors in Endometrial Cancer 86
C. Genes Regulated by Progestins in Endometrial Cancer 86
D. Transcriptional Activity of Progesterone Receptors in Endometrial Cancer 88
VI. Conclusions and Perspectives of Progesterone Action in Endometrial Cancer 
89 
VII. Uterine Leiomyoma 89
VIII. Progesterone Receptor Action in Leiomyoma 90
A. Relevance of Progesterone in Uterine Leiomyomas 90
B. Progesterone Action on Genes Associated with Proliferation, Apoptosis, and ECM Deposition 91
C. Growth Factor Regulation in Leiomyoma by Progesterone 93
D. Activation of Signaling Pathways in Leiomyoma by Progesterone and Estrogen 94
IX. Conclusions and Perspectives on Progesterone Action in Uterine Leiomyoma 96
X. Future Directions 97
References 97
Chapter 3: Nuclear Xenobiotic Receptors: Integrating Gene Regulation to Physiological Functions 110
I. Introduction 111
II. Ligands for Nuclear Receptors 111
III. Nuclear Receptor Domain Structures 112
A. LBD and the AF-2 Domain 112
B. DNA-Binding Domain 114
C. AF-1 Domain 114
IV. Xenobiotic Receptor Functions and Their Implications in Physiology and Diseases, A Case Study 115
V. Pregnane X Receptor (PXR) 116
A. Cloning and Initial Characterization of PXR 116
B. PXR in Phase I CYP Enzyme Regulation 117
C. PXR in Phase II Enzyme Regulation 117
1. PXR 
117 
2. PXR in SULT Regulation 
118 
3. PXR in GST Regulation 
119 
D. PXR in Drug Transporter Regulation 119
E. Implications of PXR-Mediated Gene Regulation in Drug Metabolism 120
F. Endobiotic Functions of PXR 121
1. PXR in Bile Acid Detoxification and Cholestasis 
122 
2. PXR in Bilirubin Detoxification and Clearance 
122 
3. PXR in Adrenal Steroid Homeostasis and Drug-Hormone Interactions 
123 
4. PXR in Lipid Metabolism 
123 
G. Species Specificity of PXR and the Creation of ``Humanized´´ Mice 124
1. Challenges for Rodents as Drug Metabolism Models 
124 
2. Species Specificity of the Rodent and hPXR 
124 
3. Creation and Characterization of the hPXR ‘‘Humanized’’ Mice 
125 
4. Significance of Humanized Mice in Drug Metabolism Studies and Drug Development 
127 
VI. Constitutive Androstane Receptor (CAR) 127
A. Identification of CAR as the Regulator of CYP2B Genes 127
B. CAR in the Regulation of Other DMEs 128
1. CAR Regulation of CYP2C Genes 
128 
2. CAR Regulation of UGT1A1 Genes 
129 
3. CAR Regulation of Drug Transporters 
129 
C. Mechanism of CAR Activation 130
D. Species Differences in the Activation of CAR 131
VII. Concluding Remarks 132
Acknowledgments 132
References 132
Chapter 4: Emerging Roles of the Ubiquitin Proteasome System in Nuclear Hormone Receptor Signaling 
140 
I. Introduction: Nuclear Hormone Receptors, Ubiquitin, and the Proteasome 141
II. The Ubiquitin Proteasome System 141
III. Nuclear Receptor Interactions with the Ubiquitin Proteasome System 143
A. Nuclear Receptor Protein Stability, Targeting by the Ubiquitin Proteasome System and Influences of Ligand on Nuclear Receptor Protein Degradation 
143 
B. Role of the Ubiquitin Proteasome System in Nuclear Receptor-Mediated Transcription 144
IV. Coregulators and the UPS 146
V. Coregulators as UPS Targets 148
VI. Ubiquitin-Like Modifications in Nuclear Receptor Signaling 151
VII. Conclusion and Perspective 152
References 152
Chapter 5: Biochemical Analyses of Nuclear Receptor-Dependent Transcription with Chromatin Templates 
160 
I. Nuclear Receptors (NRs): Transcription Factors (TFs) with Separable Biochemical Activities 161
II. Biochemical Analyses of NR Activities, Interactions, and Functions: An Historical View 162
A. Elucidation of NR Biochemical Activities 162
B. NRs and the RNA Polymerase II Transcription Machinery 162
C. NR Coregulators 163
D. Transcriptional Regulation by NRs: Early Studies 165
III. Role of Chromatin in NR-Dependent Transcription 166
A. Chromatin: The Physiological Template for NR-Dependent Transcription 166
B. Linking NR Function to Chromatin 167
IV. Biochemical Methods for the Analysis of NR-Dependent Transcription 168
A. Components of Activator-Dependent In Vitro Transcription Systems 168
B. DNA Templates 169
C. Transcription Machinery 170
D. Detection of Transcripts 170
E. Purification of NR and Coregulator Proteins 171
V. Biochemical Methods for the Assembly and Analysis of Chromatin 172
A. DNA Templates 172
B. Histones 172
C. Methods for Assembling Chromatin In Vitro 174
1. Salt Dilution/Dialysis Chromatin Assembly Systems 
174 
2. Extract-Based Chromatin Assembly Systems 
175 
3. Defined Chromatin Assembly Systems 
176 
D. Methods for Analyzing Chromatin Assembled In Vitro 177
1. Nuclease Digestion of Chromatin Assembled In Vitro 
177 
2. Analysis of the Physical Properties of Chromatin Assembled in vitro 
178 
3. Imaging of Chromatin Assembled in vitro 
179 
E. Putting It All Together: In Vitro Transcription with Chromatin Templates 179
VI. What have We Learned About NR-Dependent Transcription from In Vitro Chromatin Assembly and Transcription Studies? 180
A. Role of Ligands 180
1. Agonist Ligands are Required for NR-Dependent Transcription with Chromatin Templates 
180 
2. Agonist Ligands Promote Productive Interactions with NR Coregulators 
181 
B. Role of Basal TFs 182
C. Role of Coactivators 183
1. p 
183 
2. p300 and CBP Acetyltransferases 
184 
3. Other HMEs 
185 
4. ATP-Dependent CRCs 
186 
5. Mediator 
187 
D. Role of Corepressors 188
E. Role of Nucleosome-Binding Proteins 189
F. Order and Dynamics 191
1. Temporal Aspects of NR-Dependent Transcription 
191 
2. Initiation and Reinitiation 
195 
3. Kinetics of NR Binding to Chromatin 
197 
VII. Future Directions 197
A. Repression of Transcription by NRs 198
B. Single Molecule Studies 198
C. NR Biochemistry in the Postgenomic Era 199
VIII. Summary 201
References 201
Chapter 6: Chromatin Remodeling and Nuclear Receptor Signaling 216
I. Introduction 217
II. NR Classification and Structure 217
A. NR Classification 218
B. NR Structure 219
III. NR Coregulators 220
A. Coactivators 221
B. Corepressors 221
1. NCoR/SMRT Structure 
222 
2. NCoR/SMRT Complexes 
223 
IV. Chromatin as an NR Coregulator Substrate 224
A. Nucleosomes: The Basic Unit of Chromatin 225
B. Post-translational Histone Modifications and the Histone Code 226
1. Histone Acetylation 
227 
2. Histone Methylation 
228 
C. Role of INHATs in NR Signaling and Beyond 228
D. Nucleosomes in Gene Regulation 233
V. ATP-Dependent Chromatin Remodelers in NR Gene Regulation 235
A. Overview 235
B. SWI/SNF Complexes and NR Regulation 235
1. Coactivation of Class I NRs by SWI/SNF 
236 
2. The VDR–WINAC Connection 
237 
C. Acf1 and ISWI Complexes and NR Regulation 239
1. ISWI Complexes and NR Activation 
240 
2. ISWI Complexes and NR Repression 
241 
VI. Future Directions 245
Acknowledgments 
247 
References 248
Chapter 7: Nuclear Receptor Repression: Regulatory Mechanisms and Physiological Implications 
258 
I. Introduction 259
II. Corepressors 261
A. Ligand-Independent Corepressors 261
B. Ligand-Dependent Corepressors 263
III. Types of NR Repression 264
A. Repression by Unliganded Receptors 264
B. Repression by Antagonist-Bound Steroid Receptors 265
C. Repression by Agonist-Bound Receptors 266
IV. Molecular Mechanisms of Transcriptional Repression 267
A. Histone Deacetylation 267
B. Histone Methylation 268
C. Chromatin Assembly/Remodeling 269
D. DNA Methylation 270
V. Physiological Functions of NR-Mediated Repression 271
A. Physiological Function of Repression by Unliganded TR 271
B. TR-Mediated Repression in the Regulation of Amphibian Metamorphosis 272
C. Repression by PPARgamma 272
D. Repression Mediated by NCoR and SMRT 273
E. Repression Mediated by RIP140 274
VI. Concluding Remarks 275
Acknowledgments 
275 
References 276
Chapter 8: The 
284 
I. Introduction: The Discovery of AIB1/ACTR/SRC-3 as a Nuclear Hormone Receptor Coactivator and a Gene Amplified in Cancer 
285 
II. Aberrant Genetic Regulation of p160/SRC Expression in Cancers 287
A. Chromosomal Alterations 287
1. Gene Amplification of AIB1 and SRC-1 
287 
2. ChromosomalTranslocation and Inversion Involving the SRCs 
290 
B. Polymorphisms 293
1. Single Nucleotide Polymorphisms (SNPs) 
293 
2. Variable Number of Polyglutamine Repeats 
294 
C. Aberrant Expression of SRCs in Cancers and the Potential Underlying Mechanisms 295
1. Overexpression in Cancers and the Disease Implications 
295 
2. Transcriptional Deregulation of AIB1/ACTR Gene 
296 
III. The p160/SRCs Functions and Their Action Mechanisms in Cancer Cells 298
A. Cell Proliferation, Survival, Invasion, and Metastasis 298
1. Hormone-Dependent and -Independent Proliferation of Prostate and Breast Cancer Cells: p160 Coactivators as Mediators of Ets, 298
2. IGF/Akt Signaling and Pathway Components-Direct and Indirect Targets for AIB1/ACTR-Mediated Survival 
300 
3. Invasion and Metastasis Mediated by AIB1/ACTR, AP-1, and PEA3 
302 
B. Tamoxifen Resistance in Breast Cancer 304
1. AIB1/ACTR and HER2 Overexpression Promote Tamoxifen Resistance 
304 
2. AIB1/ACTR Cooperates with Ets Family Members to Potentiate HER2 Signaling 
305 
3. AIB1/ACTR Activates E2F-Regulated Cell Proliferative Program in the Presence of Tamoxifen 
305 
4. An AIB1/ACTR Isoform may Promote Agonist Activity of Tamoxifen 
305 
5. SRC-1 is Involved in Agonistic Activity of Tamoxifen 
306 
C. Androgen Independence in Prostate Cancer 306
1. p160 Coactivator Levels are Altered by Androgen Ablation to Facilitate Ligand-Dependent and -Independent AR Activation 
307 
2. AR Mutations and Kinase Signaling can Increase Ligand and p160 Coactivator Binding Affinity 
308 
IV. Functions of p160/SRCs in Tumorigenesis Revealed in Animal Models 309
A. SRCs in Mouse Mammary Tumorigenesis and Tumor Metastasis 309
B. SRC-3 in the Mouse Prostate Cancer Model 310
V. The Coregulator ANCCA, a Unique Target of AIB1/ACTR and a Potential Key Player in Cancer 311
A. ANCCA is a Hormone-Induced Nuclear Receptor Coregulator and a Target of AIB1/ACTR 311
B. ANCCA, a Potential Key Player in Tumorigenesis, is Frequently Overexpressed in Different Cancers 312
VI. Concluding Remarks 313
Acknowledgments 
313 
References 314
Chapter 9: Protein Arginine Methyltransferases: Nuclear Receptor Coregulators and Beyond 
322 
I. Introduction 323
II. Enzymatic Activity of PRMTs 324
A. PRMTs Catalyzing Asymmetric Dimethylation (Type I) 324
B. PRMTs Catalyzing Symmetric Dimethylation (Type II) 326
C. PRMTs Without Identified Activity 327
D. Distributive Versus Processive Mechanism 327
E. Substrate Specificity and Regulation 328
F. Posttranslational Regulation of PRMTs 329
III. PRMTs in Transcriptional Regulation 330
A. PRMTs as Histone Methyltransferases 330
1. Histone Modification Catalyzed by Type I PRMTs 
330 
2. Histone Modification Catalyzed by Type II PRMTs 
331 
3. Histone Arginine Demethylation 
332 
B. PRMTs Involved in Nuclear Receptor Regulation 333
1. CARM1 as a Model Coactivator for Nuclear Receptor Transcription 
333 
2. Coactivators Methylated by CARM1 
334 
3. The Nonsubstrate CARM1 Interacting Proteins 
335 
4. Other PRMTs-Nuclear Receptor Interactions 
336 
C. PRMTs Regulate Transcription Mediated by Other Transcription Factors 337
1. PRMT1 
337 
2. CARM1 338
3. PRMT5 
338 
D. Interplay of PRMTs During Transcriptional Regulation 339
1. p53 
339 
2. NF-kappaB 
340 
3. E2Fs 
340 
E. PRMTs in Transcription Elongation 341
IV. PRMTs in Posttranscriptional Regulation 341
V. Structural Analysis of PRMTs 342
VI. Small Molecule Inhibitors for PRMTs 346
VII. Biological Functions of PRMTs 347
A. PRMTs in Differentiation and Development 348
1. PRMTs in Muscle Differentiation 
348 
2. PRMTs in Precursor Maintenance 
349 
3. PRMTs in Development-What We have Learned from Mouse Models 
349 
B. PRMTs in Cancer 350
C. PRMTs in Viral Infection and Immune Response 351
D. PRMTs in Metabolism 352
1. PRMTs in Glucose Metabolism 352
2. PRMTs in Adipogenesis 
352 
E. PRMTs and DNA Methylation 353
F. PRMTs and DNA Repair 353
G. PRMTs and Chromatin Domains 354
VIII. Concluding Remarks 355
Acknowledgments 
355 
References 355
Chapter 10: Roles of Histone H3-Lysine 4 Methyltransferase Complexes in NR-Mediated Gene Transcription 
366 
I. Introduction 367
II. Activating Signal Cointegrator-2 (ASC-2) 369
A. Expression of ASC-2 and Its Isoforms 370
B. Autonomous Transactivation Domains of ASC-2 371
C. Two NR Boxes in ASC-2 371
1. NR1 
372 
2. NR2 372
D. Homodimerization Domain in ASC-2 373
III. Set1-Like H3K4MT Complexes 374
A. Methylation of H3K4 374
B. Multiple Set1-Like H3K4MT Complexes in Vertebrates 374
C. A Subcomplex of WDR5, RbBP5, and ASH2L in Set1-Like Complexes 375
D. H3K4 Methyl-Binding Effectors 376
IV. ASCOM in NR-Mediated Transactivation 377
A. ASCOM-MLL3 and ASCOM-MLL4 377
B. ASCOMs as Crucial H3K4MT Complexes for a Subset of NRs 378
C. Recruitment of Set1-Like H3K4MT Complexes 379
V. Cross Talk of ASCOMs with Other Coactivators 380
A. CBP/p300 381
B. RNA-Binding Proteins 382
C. Swi/Snf 383
VI. Physiological Roles of Key Subunits of ASCOM 385
A. ASC-2 385
1. DN1 and DN2 
385 
2. ASC-2 Mutant Mice 
385 
3. 129S6 Isogenic ASC-2+/- Mice 
387 
4. Phenotypes from Conditional Knockouts 
388 
B. Metabolic Phenotypes of MLL3 389
1. WAT Phenotypes of MLL3Delta/Delta Mice 
390 
2. Lipid And Bile Acid Phenotypes of MLL3Delta/Delta Mice 
390 
C. ASCOM in Cancers 392
1. Amplification and Overexpression of ASC-2 in Human Cancers 
393 
2. Mammary Tumor Suppressive Function of ASC-2 
393 
3. ASCOM as a Coactivator of the Tumor Suppressor p53 and Kidney Phenotypes of MLL3Delta/Delta Mice 
393 
VII. Future Challenges 395
Acknowledgments 
397 
References 397
Index 
406 

Produkt-Details

• Erscheint lt. Verlag: 25.7.2009
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Anatomie / Neuroanatomie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Themenwelt: Technik
• ISBN-10: 0-08-091198-6 / 0080911986
• ISBN-13: 978-0-08-091198-4 / 9780080911984