Nutrients and Cell Signaling (Oxidative Stress and Disease)

Front cover......Page 1
Series Introduction......Page 7
Preface......Page 11
Contributors......Page 13
Contents......Page 21
Nuclear Receptors, Transcription Factors, and Signaling Cascades......Page 25
Introduction......Page 27
Activation of the IKK......Page 28
Modulation of NFkB Transcriptional Activity......Page 29
The IL-1/Toll Receptor Superfamily......Page 30
IL-1R-Mediated NFkB Activation......Page 31
TLR3-Mediated NFkB Activation......Page 33
Negative Regulation of Toll-IL-1R-Mediated Signaling......Page 34
Effect of NFkB Activation in Stress Responses......Page 35
Stress-Induced NFkB Activation through IKK-Independent Pathways......Page 36
NFkB Activation by the TNF Receptor Superfamily......Page 37
A Protective Role for NFkB in Signal-Induced Cell Death......Page 39
NFkB Activation upon BCR and TCR Engagement......Page 40
Constitutive Activation of NFkB in Human Cancers......Page 41
Future Directions......Page 42
References......Page 43
Introduction......Page 59
The Endocrine System and Endocrine Disruption......Page 60
Hormone Dynamics......Page 61
Molecular Mechanics of Endocrine Action: Receptor-Based Mechanisms......Page 62
The Estrogen Receptors (ERs)......Page 63
Tissue Differences in ER Distribution in Adults......Page 64
Receptors and “Ligand Cross Talk”......Page 66
Disease Scenarios: A Question of Receptor Balance or Imbalance?......Page 67
ERb and Men......Page 69
The Many Biological Roles of ERb......Page 70
ERb and Ovarian Cancer......Page 71
Dietary Exposure: Synthetic Estrogens vs. Phytoestrogens......Page 72
Receptors Interacting with Cytochrome P450 Enzymes: Steroidogenic Pathway and Xenobiotic Metabolism......Page 76
Key Nuclear Receptors: Multifaceted Communication Systems......Page 79
Aryl Hydrocarbon Receptor (AhR)......Page 81
Pregnane X Receptor (PXR)......Page 83
The Constitutive Androstane Receptor (CAR)......Page 85
Human Peroxisome Proliferator-Activated Receptor......Page 86
Comodulators that Enhance or Suppress Transcriptional Activity......Page 88
Receptor-Ligand Interactions......Page 89
Receptor-Receptor and Receptor-Enzyme Interactions......Page 90
Heterodimerization Partners......Page 92
Final Remarks......Page 93
References......Page 94
Introduction......Page 115
Transport of Vitamin A......Page 117
Metabolism of Vitamin A......Page 118
General Features of RARs and RXRs......Page 121
DNA-Binding Domain......Page 123
Ligand-Binding Domain......Page 124
A and B Domains......Page 128
Dimerization......Page 129
Coactivactor and Corepressors......Page 131
Expression Pattern of RARs and RXRs......Page 132
RAR and RXR Knockout Studies......Page 133
References......Page 135
Abbreviations......Page 151
Introduction......Page 152
Synthetic Analogs of 1,25(OH)2D3......Page 153
T Lymphocytes......Page 155
Antigen-Presenting Cells: Monocytes, Macrophages, and Dendritic Cells......Page 156
Effects of Vitamin D Deficiency on the Immune System......Page 160
Molecular Pathways of 1,25(OH)2D3-Mediated Immune Regulation......Page 161
In vivo Immunomodulatory Potential of 1,25(OH)2D3 and Its Analogs......Page 164
In Vivo Use of 1,25(OH)2D3 Analogs......Page 165
Synergism with Other Immunosuppressants......Page 169
Combination with Bone-Resorption Inhibitors......Page 172
Conclusions......Page 173
References......Page 175
Forms and Functions of Vitamin D......Page 189
Vitamin D Deficiency......Page 190
Metabolism of Vitamin D......Page 191
Mechanisms of Vitamin D Action......Page 194
Newly Identified Vitamin D Target Cells......Page 196
Antiproliferative Effects of 1,25(OH)2D3......Page 197
Induction of Differentiation by 1,25(OH)2D3......Page 200
Regulation of Apoptotic Pathways by 1,25(OH)2D3......Page 202
Summary......Page 205
References......Page 206
Introduction......Page 217
The Identification of Growth-Arrest Genes......Page 218
Growth-Arrest Genes Activated by the Inhibition of DNA Synthesis and Dependent on the p53 System (gas1 and gadd45)......Page 219
Endoplasmic Reticulum Stress Responses (gadd153/CHOP and gadd34)......Page 223
RNA Processing (gas5), a Member of the 5TOP Gene Family......Page 227
Microfilaments and Microtubules......Page 228
Transmembrane Proteins......Page 229
Secreted Proteins......Page 230
Concluding Remarks......Page 232
References......Page 234
Introduction......Page 249
Arginine Transport and Availability......Page 250
Calcium Availability......Page 256
Tetrahydrobiopterin Availability......Page 257
NADPH Availability......Page 258
Expression and Activity of cNOS......Page 259
Expression and Activity of iNOS......Page 262
Future Perspectives......Page 265
References......Page 266
Introduction......Page 277
Thioredoxin......Page 279
Thioredoxin Reductase......Page 281
Evolution of Thioredoxin Reductase......Page 282
Cellular Functions of Thioredoxin Reductases......Page 286
Roles in Signaling and Regulation of Thioredoxin Reductase Expression......Page 287
Redox Regulation by ROS......Page 289
References......Page 292
Introduction......Page 301
DNA Repair......Page 303
Spermatogenesis......Page 304
Enzymatic Biotinylation of Histones......Page 305
Identification of Biotinylated Histones......Page 307
Identification of Biotinylation Sites......Page 309
Cell Proliferation......Page 311
DNA Damage......Page 313
Debiotinylation of Histones......Page 314
References......Page 315
Amino Acids, Lipids, and Glycation......Page 321
Introduction......Page 323
Unique Role of Leucine in Amino Acid Regulation of mTOR and Protein Synthesis......Page 325
Important Role of mTOR......Page 328
Steps in Translation Initiation of Protein Synthesis Modified by Leucine......Page 332
Physiological Role of the Leucine Signaling to mTOR......Page 337
References......Page 338
Introduction......Page 353
Overall Effect of Amino Acids and Insulin......Page 354
Mechanism of Activation of GS and ACC......Page 355
Control of Protein Synthesis......Page 357
Overall Effects of Amino Acids and Insulin......Page 363
Amino Acid Signaling......Page 364
AMPK......Page 365
Protein Phosphatases......Page 366
Insulin and Leucine......Page 367
Conclusions......Page 368
Acknowledgments......Page 369
References......Page 370
Target of Rapamycin......Page 377
Nutrient-Dependent TOR Functions in Yeast......Page 379
S6K1 and 4EBP1 - Downstream Effectors of mTOR......Page 380
mTOR Pathway in Cell Growth and Proliferation......Page 382
Amino Acid Sensing and Mitogenic Pathways in the mTOR Network......Page 383
An Amino Acid-Sensing Complex: Raptor and GbL......Page 386
TSC1-TSC2 Complex and Rheb......Page 387
Amino Acid Sensing by mTOR in Cellular Differentiation......Page 389
Adipogenesis......Page 390
Trophoectoderm Differentiation......Page 391
Amino Acid-Sensing and Energy-Sensing Mechanisms......Page 392
Future Directions......Page 393
References......Page 394
Introduction......Page 405
The Glutamate-Glutamine Cycle......Page 406
Ammonia and Glutamate Release......Page 408
Ammonia and Glutamate Uptake......Page 409
Ammonia and Glutamine Synthetase......Page 413
Ammonia and Glutamine Release and Uptake......Page 415
Ammonia and Glutaminase......Page 416
Ammonia and Glutamate Uptake into Synaptic Vesicles......Page 417
Consequences of Ammonia-Induced Dysfunction of the Glutamate-Glutamine Cycle......Page 419
Therapeutic Implications of Ammonia-Induced Dysfunction of the Glutamate-Glutamine Cycle......Page 422
Summary......Page 423
References......Page 424
Nuclear Transport......Page 435
Fatty Acids......Page 439
Cholesterol......Page 443
Sphingolipids......Page 448
Conclusions......Page 452
References......Page 453
Biosynthesis......Page 463
Monoterpenes......Page 465
Isoprenylated Proteins......Page 466
Rap1......Page 467
Rho Proteins......Page 468
Mevalonate Depletion Upregulates Ras, Rap1a, RhoA, and RhoB......Page 469
Isoprenoids and Regulation of Ras-Related Proteins......Page 471
Isoprenoid Analogues and Regulation of Ras-Related Proteins......Page 475
Monoterpenes and Regulation of Ras-Related Proteins......Page 477
References......Page 480
Introduction......Page 485
Introduction......Page 486
Inhibition of Autophagy by Amino Acids......Page 487
Signaling, Autophagy, and Amino Acid Specificity......Page 490
The Amino Acid Sensor......Page 493
mTOR-Associated Proteins......Page 494
Polyphosphates......Page 495
Phosphatases......Page 496
PI3-Kinase Class III/Beclin1......Page 497
Erk1/2......Page 498
mTOR, Energy, and Autophagy......Page 499
Autophagy, Amino Acid Signaling, and Longevity......Page 500
Conclusions......Page 501
References......Page 503
O-GlcNAc Addition and Removal: A Signaling Modification......Page 515
Evidence for a Hexosamine Signaling Pathway......Page 516
O-Linked GlcNAc Transferase: Molecular Genetics......Page 517
Transcripts Encoding OGT......Page 518
The OGT Gene: Overall Structure and Isoforms......Page 519
Domain Structure and Posttranslational Modifications......Page 520
OGT: N-Terminal Sorting Sequences......Page 521
OGT: Linker/Nuclear Targeting Domain......Page 523
OGT: The Catalytic Domain......Page 524
Protein Complexes Containing OGT......Page 525
O-GlcNAcase: Molecular Genetics......Page 526
The O-GlcNAcase Gene and Alternatively-Spliced Isoforms......Page 527
O-GlcNAcase: Domain Structure......Page 528
The Substrates Modified by O-GlcNAc and O-GlcNAcase......Page 529
Nuclear Pore Glycoproteins......Page 530
Transcription Complexes......Page 532
Kinases and Other Enzymes......Page 533
Evolutionary Conservation of OGT and O-GlcNAcase......Page 534
GFAT......Page 536
Glucosamine-6-Phosphate (GlcN6P) Acetyl Transferase (Emeg32 or GAT)......Page 537
Hexosamine-Dependent Signaling: The Involvement of O-GlcNAcase (OGA) in Insulin Signaling......Page 538
Hexosamine-Dependent Signaling: The Involvement of OGT in Apoptosis......Page 539
The Hexosamine Signaling Pathway and Human Disease......Page 540
Summary and Conclusions......Page 541
References......Page 543
Insulin Release, Signaling, and Insulin Resistance......Page 555
Introduction......Page 557
Glucose Metabolism in the b-Cell......Page 558
Biphasic Insulin Release......Page 559
ATP-Sensitive K+ Channel-Dependent Pathway......Page 561
The KATP Channel-Independent Pathways......Page 564
Amino Acid-Induced Insulin Release......Page 567
Free Fatty Acids......Page 568
Incretin and cAMP Stimulation of Insulin Release......Page 569
Norepinephrine and Other Inhibitory Inputs......Page 572
Diabetes and Hypoglycemia......Page 573
Summary......Page 576
References......Page 577
Introduction......Page 589
The Glucagon Superfamily......Page 590
Proglucagon Expression and Processing......Page 591
Secretion and Metabolism of GLPs......Page 593
Effects on Food Intake......Page 595
Effects on Nutrient Flow in the Gastrointestinal Tract......Page 597
Effects on Nutrient Breakdown and Storage......Page 598
GLPs in Development and Adaptation......Page 600
Mechanisms of Action......Page 601
Therapeutic Potential of GLPs......Page 602
Remaining Questions......Page 603
Acknowledgment......Page 604
References......Page 605
Calcium-Dependent Signaling......Page 611
Introduction......Page 613
Voltage-Sensitive Calcium Channels (VSCC)......Page 615
Regulations of VSCC......Page 617
Feedback Control......Page 618
Capacitance Calcium Entry......Page 619
Ligand-Gated Calcium Channels......Page 620
Endogenous Regulation of VSCC......Page 623
Intracellular Storage......Page 625
Efflux of Calcium from Sarco/Endoplasmic Reticulum......Page 626
Calcium Channels, Pyridoxal Phosphate, and Cardiovascular Protection......Page 629
Calcium Channels, Pyridoxal Phosphate, and Neuroprotection......Page 631
References......Page 633
Abstract......Page 645
Introduction......Page 646
ER Calcium Homeostasis and Function......Page 647
Impairment of ER Calcium Homeostasis in Acute and Degenerative Disorders of the Brain......Page 649
ER Stress and ER Stress Response......Page 650
Indicators of ER Dysfunction in Acute and Degenerative Diseases of the Brain......Page 652
Conclusion......Page 653
References......Page 654
Feeding and Nutrient Homeostasis......Page 663
Introduction......Page 665
Episodic Events: Hunger, Satiety, and the Appetite Cascade......Page 666
Neural Structures Critical to the Expression of Appetite......Page 668
Sensory Stimuli......Page 669
Physiological Stimuli......Page 670
Preabsorptive Factors......Page 673
Postabsorptive Factors......Page 678
Integration of Episodic Signals within the CNS......Page 680
Acknowledgments......Page 682
References......Page 683
Introduction......Page 689
Anatomy......Page 690
Neuronal Populations and Connections......Page 691
Neuromodulators Present and Colocalizations......Page 692
Efferent Projections......Page 693
Periphery-CNS Communications......Page 694
Intrahypothalamic Communications......Page 695
Functional Aspects......Page 696
Fasting and Refeeding Influences......Page 698
Peptide Infusion Effects......Page 700
References......Page 702
INDEX......Page 725