Regulation of Organelle and Cell Compartment Signaling (eBook)

Front Cover 1
Regulation of Organelle and Cell Compartment Signaling 4
Copyright Page 5
Editorial Advisory Board 6
Contents 8
Preface 12
Contributors 14
Section A: Overview 20
Chapter 1: Organelle Signaling 22
Origins of Cell Signaling Research 22
Receptors and Intracellular Signaling 23
Transcriptional Responses 24
Organelle Signaling 25
Focus and Scope of this Volume 26
References 26
Section B: Nuclear Signaling 28
Part 1: Transcription 30
Chapter 2: Signaling at the Nuclear Envelope 32
Introduction 32
Lamins and Lamin Associated Proteins in Cell Signaling 33
The Npc in Cell Signaling 36
Conclusions 36
Acknowledgements 36
References 37
Chapter 3: Nuclear Receptor Coactivators 40
Introduction 40
Ligand-Dependent Interaction between Nuclear Receptors and Coactivators 40
Posttranslational Modifications Performed by Coactivator Complexes 42
Conclusions 43
References 43
Chapter 4: Corepressors in Mediating Repression by Nuclear Receptors 46
Introduction 46
Corepressors Bound to Unliganded Receptor 47
Transrepression Strategies 49
Corepressors as Metabolic Sensors 50
Disease Mechanisms of Nuclear Receptor Dependent Transrepression 51
Future Directions 52
References 52
Chapter 5: Steroid Hormone Receptor Signaling 56
Introduction 56
Activation by the Hormone 56
Hormone Independent Activation 57
Cross-Talk with Other Transcription Factors 57
Non-Genomic Action of Steroid Hormones 57
The Errs 57
Selective Steroid Hormone Receptor Modulators 58
Acknowledgements 58
References 58
Chapter 6: FOXO Transcription Factors: Key Targets of the PI3K-Akt Pathway that Regulate Cell Proliferation, Survival,and Organismal Aging 62
Introduction 62
Identification of the Foxo Subfamily of Transcription Factors 62
Regulation of Foxo Transcription Factors by the PI3K-Akt Pathway 62
Other Regulatory Phosphorylation Sites in Foxos 63
Mechanism of the Exclusion of Foxos from the Nucleus in Response to Growth Factor Stimulation 63
Transcriptional Activator Properties of Foxos 65
Foxos and the Regulation of Apoptosis 65
Foxos are Key Regulators of Several Phases of the Cell Cycle 65
Foxos in Cancer Development: Potential Tumor Suppressors 67
Role of Foxos in the Response to stress and Organismal Aging 67
Foxos and the Regulation of Metabolism in Relation to Organismal Aging 67
Conclusion 68
Acknowledgements 68
References 68
Chapter 7: The Multi-Gene Family of Transcription Factor AP-1 72
Introduction 72
General Structure of the AP-1 Subunits 72
Transcriptional And posttranslational Control of AP-1 Activity 73
Function of Mammalian AP-1 Subunits During Embryogenesis and Tissue Homeostasis: Lessons From Loss-of-Function and Gain-of-Function Approaches in Mice 74
Function of Mammalian AP-1 Subunits During Cancer Development and Progression 78
Conclusion 79
Acknowledgements 79
References 79
Chapter 8: NF.B: A Key Integrator of Cell Signaling 82
References 87
Chapter 9: Ubiquitin-mediated Regulation of Protein Kinases in NF.B Signaling 90
Introduction 90
The Ubiquitin Pathway 90
NF.B Signaling 91
Ubiquitin-Mediated Activation of Protein Kinases in the IL-1R and TLR Pathways 92
Ubiquitin-Mediated Regulation of NF.B and Apoptosis in the TNFa Pathway 93
De-Ubiquitination Enzymes Prevent Protein Kinases Activation in The NF.B Pathway 95
Polyubiquitination Regulates Protein Kinase Activation in Diverse NF.B Pathways 96
Conclusions And Perspectives 98
Acknowledgements 98
References 98
Chapter 10: Transcriptional Regulation via the cAMP Responsive Activator CREB 102
The Creb Family of Transcription Factors 102
Domain Structure and Function 102
Overview of CREB Activation 103
Key Phosphorylation Events 103
CREB Target Genes 103
CBP and P300 104
TORC 104
Other Coactivators and Interacting Proteins 104
Questions to be Addressed 105
Acknowledgements 105
References 105
Chapter 11: The NFAT Family: Structure, Regulation, and Biological Functions 108
Introduction 108
Structure and DNA Binding 108
Regulation 109
Transcriptional Functions 111
Biological Programs Regulated By NFAT 111
The Primordial Family Member: NFAT5 112
Perspectives 113
References 113
Chapter 12: JAK-STAT Signaling 118
Abbreviations 118
Introduction 118
The JAK-STAT Paradigm 118
The JAK Family 121
The STAT Family 122
A Bright Future 123
References 123
Part 2: Chromatin Remodeling 126
Chapter 13: Histone Acetylation Complexes 128
Introduction 128
KAT Classification and Diversity 129
Bromodomains and Other Interpreters of Histone Modifications 134
Kats and Disease 134
Conclusion and Future Directions 135
Acknowledgements 135
References 135
Chapter 14: Regulation of Histone Deacetylase Activities and Functions by Phosphorylation and Dephosphorylation 138
Introduction 138
Reversible Phosphorylation of Mammalian Class I Hdacs 139
Reversible Phosphorylation of Mammalian Class II Hdacs 142
Conclusion and Perspectives 144
References 145
Chapter 15: Histone Methylation: Chemically Inert but Chromatin Dynamic 148
Introduction 148
Historical Perspective of Chromatin and Histone Methylation 148
Enzymes Regulating Arginine and Lysine Methylation States 149
Histone Lysine Methyltransferases 151
Histone Demethylase Enzymes 151
Degree and Location Matter 153
References 154
Chapter 16: Histone Phosphorylation: Chromatin Modifications that Link Cell Signaling Pathways to Nuclear Function Regulation 158
Introduction 158
Histone Phosphorylation and Transcriptional Regulation 159
Downstream Effects of Transcription Associated H3 Phosphorylation 161
Histone Phosphorylation in Response to DNA Damage 162
Histone Phosphorylation and Mitosis 163
Histone Phosphorylation During Apoptosis 163
Histone Phosphorylation and Human Diseases 164
Conclusions and Perspectives 164
References 165
Chapter 17: Histone Variants: Signaling or Structural Modules? 168
Introduction 168
H2A.Bbd in Search of a Function 169
H2A.X: DNA Damage and Beyond 170
H2A.Z Function at a Flip of a Coin 171
Macro H2A: Phosphorylation Matters 172
H2B Variance and Unknown Partners 173
H3.3 Providing Transcriptional Memory 174
CENP-A: Splitting Nucleosomes in Drosophila 174
Histone H1: The Microheterogeneity of Specialized Function 176
Concluding Remarks 177
Acknowledgements 178
References 178
Chapter 18: Histone Ubiquitination 186
The Mechanism of Ubiquitination 186
Histone Ubiquitination 186
Mono-Ubiquitination of H2A 186
Ubiquitination of Histone H2A Variants 187
De-Ubiquitination of Ubh2A 188
How does UbH2A Repress Transcription? 189
The Role of UbH2A in DNA Repair 189
Mono-Ubiquitination of H2B 189
H2B Ubiquitination Requires Factors Involved in Transcription Initiation and Elongation 190
H2B Ubiquitination is Required for Processive Lys-4 H3 and Lys-79 H3 Methylation 191
The 19S Proteasome and the Ccr4-not Complex Link H2B Ubiquitination to Lys-4 and Lys-79 H3 Methylation 192
De-Ubiquitination of UbH2B 192
De-Ubiquitination of UbH2B is Required for Later Stages of Transcription Elongation 193
Conclusion 193
Acknowledgements 194
References 194
Chapter 19: Chromatin Mediated Control of Gene Expression in Innate Immunity and Inflammation 198
Introduction 198
Inflammation as a Kinetically Complex Transcriptional Response 198
Chromatin and the Kinetic Control of Inflammatory Responses 199
Genetic Dissection of Chromatin Remodeling at Inflammatory Genes 199
Binding of Inflammatory Transcription Factors to Nucleosomal DNA 200
Conclusions 202
References 203
Part 3: Stress Responses 204
Chapter 20: Complexity of Stress Signaling 206
Abbreviations 206
Introduction 206
Origin of Stress Response Signals 207
Signal Transduction 211
Systems Level Deductions of Stress Response Networks 214
Acknowledgements 217
References 217
Chapter 21: Oxidative Stress and Free Radical Signal Transduction 226
Introduction: Redox Biology 226
Oxidative Stress Responses in Bacteria: Some Well-Defined Models of Redox Signal Transduction 226
Response to Superoxide Stress and Nitric Oxide: SoxR Protein 226
Response to H2O2 and Nitrosothiols:Oxyr Protein 229
Parallels in Redox and Free Radical Sensing 230
Themes in Redox Sensing 230
Acknowledgements 230
References 231
Chapter 22: Double-Strand Break Recognition and its Repair by Non-Homologous End-Joining 234
Overview of Non-Homologous End-Joining (NHEJ) 234
Kinase Activation and Autophosphorylation of DNA-PK 234
DNA-PK May Influence the Balance of HR and NHEJ during S Phase 237
Local Chromatin Structure at Sites of NHEJ 238
References 238
Chapter 23: ATM Mediated Signaling Defends the Integrity of the Genome 240
Introduction 240
Sensing Radiation Damage in DNA 241
Atm Activation and Recruitment of DNA Damage Response Proteins to DNA DSB 242
ATM Mediated Downstream Signaling 243
Cell Cycle Checkpoint Activation 246
Concluding Remarks 248
References 248
Chapter 24: Signaling to the p53 Tumor Suppressor through Pathways Activated by Genotoxic and Non-Genotoxic Stresses 254
Introduction 254
p53 Protein Structure 254
Posttranslational Modifications to p53 256
Regulation of p53 Activity 257
p53 Stabilization 257
p53 Activation 259
Activation of p53 by Genotoxic Stresses 260
DNA Doubled-Strand Breaks 260
Replication Stress and Singlestranded DNA 261
Replicative Senescence 262
Oncogene Activation 262
Other Genotoxic Agents 263
Activation of p53 by Non-Genotoxic Stresses 263
The Unfolded Protein Response – ER Stress 263
Hypoxia 263
Glucose Deprivation – Nutritional Stress 264
Ribonucleotide Pool Imbalance 265
Nucleolar and Ribosomal Stress 265
Microtubule Disruption 266
Setting Thresholds and Resetting Activation – p53 Phosphatases 266
Conclusions 267
Acknowledgements 267
References 268
Chapter 25: The p53 Master Regulator and Rules of Engagement with Target Sequences 274
Introduction 274
The p53 Induced Transcriptional Network: Genes, Biological Functions, and the Complexity of Target Selection 274
Yeast as an in Vivo Test Tube to Study Wild-Type and Mutant p53 Transactivation Potential toward Defined Response Element Sequences 275
Yeast as an in Vivo Test Tube to Study Wild-Type and Mutant p53 Transactivation Potential Toward Defined Response Element Sequences 275
Rules of p53 Transactivation Revealed by Yeast-Based Assays 276
Spacers Affect p53 Transactivation Potential in the Yeast-Based Assay 277
Spacer Effects on p53 Binding and Transactivation in Mammalian Cell Assays 278
Non-Canonical 3/4- and 1/2-Site Res Expand the p53 Transcriptional Network 279
Impact of 1/2-Site res in the p53 Transcriptional Network 280
Evolutionary Development of p53 Res 280
Yeast Based Functional Classification of p53 Mutant Alleles Associated with Cancer 280
Contributions to the Rules of Engagement by p53 Homologs and Other Sequence Specific Transcription Factors 281
p53 Cofactors Contribute to Promoter Selectivity 281
Conclusions 281
Acknowledgements 282
References 282
Chapter 26: The Heat Shock Response and the Stressof Misfolded Proteins 286
Introduction 286
Transcriptional Regulation of the Heat Shock Response 287
Chaperone Function in Normal and Disease States 288
Acknowledgements 291
References 291
Chapter 27: Hypoxia Mediated Signaling Pathways 296
Introduction 296
HIF Regulation 296
HIF Signaling and Metastasis 297
Unfolded Protein Response 298
Conclusions 299
References 299
Chapter 28: Regulation of mRNA Turnover by Cellular Stress 302
Introduction 302
RNA-Binding Proteins Controlling mRNA Turnover 302
mRNA Decay Determinants and Degradation Machineries 304
Stress-Activated Signaling Molecules that Regulate mRNA Turnover 305
Concluding Remarks 307
Acknowledgements 307
References 307
Chapter 29: Oncogenic Stress Responses 312
Introduction 312
Downstream Effectors of OIS 312
p38Mapk Signaling and OIS 314
DNA Damage Response and OIS 315
Concluding Remarks 316
References 316
Chapter 30: Ubiquitin and FANC Stress Responses 320
Introduction 320
Components of the Fanconi Anemia Pathway 320
The FA Core Complex and Activation of the FA Pathway 320
Mono-Ubiquitylation of FANCD2 and FANCI 322
Downstream Effectors and Interactions with other DNA Repair Proteins 323
De-Ubiquitylation of FANCD2 and FANCI 325
Non-Repair Functions of the FA Pathway 325
Conclusions 326
References 326
Chapter 31: Stress and .-H2AX 328
Introduction 328
Stress Induces DNA DSB Damage and .-H2AX Formation 328
Role Of . -H2AX In DNA Damage Repair Pathways 331
. -H2AX, a Marker to Monitor Cell Stress and a Protein Involved in Stress Signaling 333
Conclusions 334
Acknowledgements 334
References 334
Section C: Signaling to/from Intracellular Compartments 338
Chapter 32: Regulation of mRNA Turnover 340
Introduction 340
Current Model for MRNA Decay in Mammalian Cells 340
Deadenylation: The First Major Step Triggering mRNA Decay 341
Regulation of Deadenylation by a Protein that Interacts with Both Poly(A) Nuclease(S) and PABP 341
A Mechanism for Translationally Coupled mRNA Turnover 342
The Involvement of RNA Processing Bodies (P-Bodies) in Regulation of mRNA Turnover 342
Concluding Remarks 343
References 343
Chapter 33: Signaling to Cytoplasmic Polyadenylation and Translation 346
Introduction 346
The Biochemistry of Cytoplasmic Polyadenylation 346
Signaling to Polyadenylation 347
A Hierarchy of Translation Control 348
Polyadenylation in Mammalian Oocytes 348
Signaling to Polyadenylation in the Brain 348
Conclusions 348
References 349
Chapter 34: Translation Control and Insulin Signaling 352
Introduction 352
The Insulin Signaling Pathway 352
Insulin Signaling and Regulation of Translation Initiation 353
Insulin Signaling and Regulation of Translation Elongation 355
Insulin Signaling and Ribosome Biogenesis 355
Concluding Remarks 356
Acknowledgements 356
References 356
Chapter 35: Signaling Pathways that Mediate Translational Control of Ribosome Recruitment to mRNA 358
Introduction 358
Translation Initiation 358
The eIF4F Complex 359
Regulation of Translation Initiation by mTOR 359
Translation and Cancer 361
Conclusions 361
References 362
Chapter 36: Nuclear and Cytoplasmic Functions of Abl Tyrosine Kinase 366
Introduction 366
Functional Domains of ABL 366
Proteins that Interact with ABL 367
ABL in Signal Transduction 369
Future Prospects 371
Acknowledgement 371
References 371
Chapter 37: The SREBP Pathway: Gene Regulation through Sterol Sensing and Gated Protein Trafficking 374
SREBPS: Membrane Bound Transcription Factors 374
Scap: Sterol Sensor and Escorter of SREBP from ER to Golgi 375
Insig: Sterol Sensor and ER Retention Protein 376
Scap and Insig: Two Sensors for Two Classes of Sterols 377
Future Challenges 377
Acknowledgements 378
References 378
Chapter 38: Ubiquitination/Proteasome 380
Protein Degradation and the Ubiquitin/Proteasome System 380
Regulation of Ubiquitination by Substrate Modification 380
Regulation of Ubiquitin Ligase Activity 382
Processing of TFS by the Ubiquitin System 382
Modulation of Kinase Activity by Ubiquitination 383
Role of Ubiquitination/Proteasome in TF Activity 383
Conclusion 384
Acknowledgements 384
References 384
Chapter 39: Regulating Endoplasmic Reticulum Function through the Unfolded Protein Response 386
Introduction 386
Molecular Sensors 386
How Molecular Sensors Detect ER Stress 387
Downregulating the UPR 388
Cellular Effects of UPR Induction 389
Physiological UPR 393
Perspectives 396
References 396
Chapter 40: Protein Quality Control in the Endoplasmic Reticulum 402
Introduction 402
ER Quality Control 402
Unique Environment of the ER 402
Molecular Chaperones and Folding Enzyme 403
Disposal of Unfolded and Misfolded Protein 404
ER Subcompartments 405
References 405
Chapter 41: Protein Quality Control in Peroxisomes: Ubiquitination of the Peroxisomal Targeting Signal Receptors 408
Introduction 408
PTS (Co-) Receptor Ubiquitination: Conundrum and Confusion 409
S. Cerevisiae PEX18P is Degraded in an Ubiquitin Dependent Manner 409
S. Cerevisiae PEX5P, Two Distinct Ubiquitination Events, Two Distinct Functions 410
The Ubiquitination of P. Pastoris PEX20P: Two Independent Ubiquitination Events? 412
Involvement of the Ring Proteins in PTS (Co-) Receptor Ubiquitination 413
AAA Protein Mediated (Co-) Receptor Recycling: an Ubiquitin Dependent Event? 413
Conclusions 414
References 415
Chapter 42: Mitochondrial Dynamics: Fusion and Division 418
Introduction 418
Mitochondrial Fusion 418
Mitochondrial Division 419
Conclusions 420
Acknowledgements 420
References 420
Chapter 43: Signaling Pathways from Mitochondria to the Cytoplasm and Nucleus 424
Introduction 424
Small Molecules as Signals from Mitochondria 424
Small Cations: NA+, K+, MG+2, CA+2, H+ 425
ATP, ADP, and AMP 425
NADH and NAD+ 426
Glutathione (GSH and GSSG) 426
Reactive Oxygen Species 427
Iron Sulfur Clusters 428
Sirtuins 428
Mitochondrial Retrograde Signaling 428
Conclusion 430
References 430
Chapter 44: Quality Control and Quality Assurance in the Mitochondrion 432
Introduction 432
Quality Assurance Mediated by Chaperones and the Protein Translocation Complex 433
Quality Control of Protein Structure and Function Mediated by ATP Dependent Proteases 437
Perspective 439
Acknowledgements 439
References 439
Chapter 45: Mitochondria as Organizers of the Cellular Ca2+ Signaling Network 444
Introduction 444
Fundamentals 444
The Plasticity of the Mitochondrial Ca2+ Handling Machinery 445
Mitochondrial Ca2+ Handling in the Cellular Context 446
CODA 451
Acknowledgements 451
References 451
Chapter 46: Signaling during Organelle Division and Inheritance: Peroxisomes 454
Introduction to Peroxisomes 454
Peroxisome Division 455
Peroxisome Inheritance 456
Concluding Remarks 458
Acknowledgements 458
References 458
Chapter 47: Bidirectional Crosstalk between Actin Dynamics and Endocytosis 462
Introduction 462
From Actin to Endocytosis 462
Converging Molecular Machinery in Endocytosis and Actin Dynamics 465
From Endocytosis to Actin Dynamics 468
Outlook 468
Acknowledgements 469
References 469
Chapter 48: Signaling in Autophagy Related Pathways 474
Introduction 474
Signaling Control of Autophagy 474
Autophagy and Cell Death 476
Acknowledgements 477
References 477
Section D: Cell Cycle/Cell Death Signaling 480
Chapter 49: Regulation of Cell Cycle Progression 482
Introduction 482
Cyclins Define Cell Cycle Phase 482
Signals to Slow Progress: Regulation of CDKs by Inhibitory Proteins 485
CDKs are Positively and Negatively Regulated by Phosphorylation 485
Degradation: The Importance of Being Absent 486
Checkpoint Signaling 487
Lessons from Mice: Cell Division without CDKs 487
Knockout Mouse Models: Cycling without Cyclins 488
References 488
Chapter 50: The Role of Rac and Rho in Cell Cycle Progression 492
Introduction 492
Regulation of G1 Progression 492
The Function of RAC and RHO in Cell Cycle Progression and Transformation 493
Cell Cycle Targets of RAC and RHO 493
Future Perspectives 494
Acknowledgement 494
References 494
Chapter 51: The Role of Alternative Splicing During the Cell Cycle and Programmed Cell Death 496
Introduction 496
Apoptosis and Splicing 496
Cell Cycle and Splicing 497
Conclusions 498
References 499
Chapter 52: Cell-Cycle Functions and Regulation of Cdc14 Phosphatases 502
Introduction 502
The CDC14 Phosphatase Subgroup of PTPs 502
Budding Yeast CDC14 is Essential for Exit from Mitosis 503
Fission Yeast CDC14 Coordinates Cytokinesis with Mitosis 504
Potential Cell-Cycle Functions of Human CDC14A and B 504
References 505
Chapter 53: Caspases: Cell Signaling by Proteolysis 508
Protease Signaling 508
Apoptosis and Limited Proteolysis 508
Caspase Activation 509
Regulation by Inhibitors 510
References 511
Chapter 54: Apoptosis Signaling: A Means to an End 514
Introduction 514
The End of the Road 514
Caspase-8 Activation via Death Receptors 515
Mitochondria and the Activation of Caspase-9 517
Mitochondrial Outer Membrane Permeabilization 518
The BCL-2 Family 518
Cell Cycle Versus Apoptosis 520
Conclusions 520
References 520
Chapter 55: The Role of Ceramide in Cell Regulation 524
Introduction 524
Sphingolipid Metabolism 524
Apoptosis 525
Non-Apoptotic Ceramide Biology 529
Conclusions 529
References 530
Index 536