Part I Metabolic Syndromes
1 Introduction ................................................ 3
1.1 The Cellular Signaling Machinery Makes Homeostasis
Possible .............................................. 4
1.2 Inflammation Is Present in Diseases ................... 4
1.3 Cholesterol Together with Inflammation Promotes
Atherosclerosis ....................................... 6
1.4 Signaling Pathways Responsible for Maintaining
Cellular Homeostasis Are Uncovered and Explored ....... 6
1.5 Biophysical Techniques Provide Detailed Information
on the Three-Dimensional Structure of
Macromolecules ........................................ 7
1.6 Signaling Pathways Have Been Illuminated Through
Intensive Efforts Spanning the Last 50 Years .......... 8
1.7 Mutated, Misfolded Proteins Cause Cancer .............. 9
1.8 The Microenvironment Is an Important Ingredient in
Cancer Metastasis .................................... 10
1.9 Neurons Are Cells Highly Specialized for Long-Range
Signaling ............................................ 12
1.10 Amyloids Are an Essential Ingredient in Many
Diseases ............................................. 12
1.11 Reactive Oxygen and Nitrogen Species Carry Out
Signaling in Ways That Contribute to Health and
Disease .............................................. 15
Further Reading ............................................ 15
2 Energy Balance ............................................. 19
2.1 Hormonal Signaling by the Endocrine Pancreas ......... 21
2.2 In Response to Signals from the Pancreas, the Liver
Maintains Glucose and Lipid Homeostasis .............. 22
2.3 Energy in the Form of Lipids Is Stored and Released
When Needed in Adipose Tissue ........................ 24
2.4 Adipose Tissue Functions as an Endocrine Organ ....... 25
2.5 Ghrelin Released by Endocrine Cells in the Stomach
Acts in Short-Term Feeding and Long-Term Energy
Management ........................................... 26
2.6 Satiation Signals Are Sent by Cells in the
Gastrointestinal Tract ............................... 26
2.7 Brown Adipose Tissue Carries Out Adaptive (Diet-
Induced and Cold-Induced, Nonshivering)
Thermogenesis ........................................ 27
2.8 Muscle Cells and β-Oxidation ......................... 29
2.9 AMPK Is an Intracellular Energy Sensor and
Regulator ............................................ 31
2.10 AMPK Is Activated by Upstream Kinases and by
Depleted Energy Supply as Indicated by Increased
AMP/ATP Ratios ....................................... 33
2.11 The Hypothalamic Network Provides Feedback Signals
to Peripheral Tissues ................................ 35
2.12 Leptin Signaling and Regulation of Energy Balance
in the Hypothalamus .................................. 37
2.13 Ghrelin Signaling and Regulation of Energy Balance
in the Hypothalamus .................................. 39
Further Reading ............................................ 40
3 Insulin Signaling and Type 2 Diabetes ...................... 45
3.1 Type 2 Diabetes Develops in a Series of Stages
from Overnutrition ................................... 46
3.2 Adipose Tissue Functions as an Immune Organ .......... 47
3.3 Metabolic Overload Occurs in Energy-Responsive
Tissues .............................................. 48
3.4 Signal Transduction Begins with the Insulin
Receptor and Its Substrate Proteins .................. 50
3.5 Phosphoinositide-3-OH Kinase (PI3K) and the PTEN
Lipid Phosphatase .................................... 52
3.6 Activation of Protein Kinase В (PKB) and Protein
Kinase С (PKC) ....................................... 54
3.7 GLUT4 Transport Biomechanics and Regulation .......... 56
3.8 The TOR Cassette Is the Downstream Target of Akt
Signals .............................................. 58
3.9 Feedback Regulation of Akt by TORC2 and IRS by
TORC1/S6K ............................................ 60
3.10 Insulin Resistance Develops from Inflammation and
Metabolic Overload ................................... 60
3.11 Glucose-Stimulated Hormone Release by Pancreatic
Islet Cells .......................................... 63
3.12 КATP Channels and Their Regulation by Cellular
Fuel Status .......................................... 65
3.13 Islet β-Cell Failure and Diabetic Complications ...... 66
Further Reading ............................................ 67
4 Metabolic Program Execution and Switching .................. 71
4.1 Nuclear Receptors Are Ligand-Activated
Transcription Factors ................................ 71
4.2 Nuclear Receptors Contain Five or Six Domains ........ 73
4.3 The CAR Activates and Deactivates in a Manner
Distinct from Other Nuclear Receptors ................ 74
4.4 Peroxisome Proliferator-Activated Receptors Are
Lipid Sensors and Effectors .......................... 75
4.5 Nuclear Receptors Require Coactivators and
Corepressors ......................................... 77
4.6 PGC-1 Scaffold Protein in Regulation of Lipid
Homeostasis .......................................... 80
4.7 FoxOs Mediate Survival, Metabolic, and Stress
Responses ............................................ 80
4.8 14-3-3 Protein Function as Small, Mobile
Phosphoprotein Binding Modules ....................... 82
4.9 Gluconeogenesis in the Liver Is Stimulated by
Glucagon and Repressed by Insulin .................... 83
4.10 Catecholamine Signaling Targets PGClα to Promote
Diet-Induced Thermogenesis in Brown Adipose Tissue ... 85
4.11 Caloric Restriction Extends Lifespan by Activating
Protective Stress Responses .......................... 86
4.12 SIRT1 Promotes Fatty Acid Oxidation in Liver and
Skeletal Muscle ...................................... 87
Further Reading ............................................ 88
5 Cholesterol ................................................ 91
5.1 Membrane Lipids Form Gels and Liquid States .......... 91
5.2 Feedback Regulation of Cholesterol Synthesis by
Insigs ............................................... 94
5.3 Feedback Regulation of Cholesterol Synthesis by
SREBPs ............................................... 95
5.4 SREBPs, Liver X Receptors, and Farnesoid X
Receptors Regulate Transcription ..................... 97
5.5 Lipoproteins Are Carriers of Cholesterol and
Triglycerides ........................................ 98
5.6 Apolipoproteins are Amphipathic, Lipid-Binding
Constituents of the Lipoproteins ..................... 99
5.7 Cholesterol Comes in Two Forms - As a Sterol, i.e.,
as a Free Cholesterol (FC) Molecule, and as a
Cholesterol Ester (CE) .............................. 102
5.8 ABC Transporters Export Cholesterol from
Macrophages ......................................... 103
Further Reading ........................................... 104
6 Atherosclerosis ........................................... 107
6.1 The Arterial Wall Consists of Three Layers .......... 107
6.2 Cells Are Continually Subjected to Forces ........... 109
6.3 Atherosclerotic Lesions Occur Preferentially in
Regions of Disturbed Blood Flow ..................... 110
6.4 Cells Utilize Multiple Mechanotransduction
Pathways That Convey Information About Blood Flow ... 112
6.5 Mechanotransduction Pathways Relay Information
About Blood Flow to Endothelial Caveolae and
Nitric Oxide Synthase ............................... 112
6.6 oxLDL Is Atherogenic and Acts in Opposition to
eNOS and NO ......................................... 113
6.7 Cell Adhesion Molecules and Chemokines Mediate
Leukocyte Migration into Sites of Inflammation ...... 115
6.8 Leukocyte Migration Occurs Through a Multistep
Adhesion Cascade .................................... 117
6.9 Selectins Are Key Mediators of Leukocyte Tethering
and Rolling ......................................... 118
6.10 Slip and Catch Bonds Play Important Roles in
Selectin-Mediated Rolling ........................... 119
6.11 Leukocyte Arrest Through the Joint Actions of
Chemokines and Integrins ............................ 121
6.12 Epithelial Cell-to-Cell Adhesions Are Maintained
by Junctional Complexes ............................. 123
6.13 Leukocytes Enter the Intima by Passing In-Between
Epithelial Cells and by Passing Through Them ........ 125
6.14 Rupture of the Fibrous Cap and Not the Lesion
Itself Causes Thrombosis ............................ 126
Further Reading ........................................... 128
7 Chronic Inflammation ...................................... 131
7.1 The NF-кВ Signaling Node Consists of IKKs, IkBs,
and NF-kBs .......................................... 132
7.2 Protein Ubiquitination Plays a Central Role in
Cellular Signaling .................................. 135
7.3 TNFα Signaling Occurs Through Complex I and
Complex II .......................................... 137
7.4 Reactive Oxygen Species (ROS) Influences the
Choice Between Survival and Death ................... 138
7.5 Toll-like Receptor 4 Responds to Bacterial
Lipopolysaccharides and Mammalian Lipids ............ 139
7.6 Downstream and into the Nucleus with NF-kBs ......... 141
7.7 Glucocorticoids Terminate Inflammatory Responses
and Restore Homeostasis ............................. 142
7.8 LXRs and PPARγ in Transrepression of Inflammation
Through SUMOylation ................................. 143
7.9 The Local Microenvironment Is a Key Organizational
Unit in Health and Disease .......................... 145
7.10 The Inflammatory Response Is a Biphasic One with
Distinct Clear Up and Reconstruction Phases ......... 146
7.11 Macrophages Are Inflammatory Cells with Key Roles
in the Body's Response to Infection and Injury ...... 147
7.12 Fibroblasts Are Connective Tissue Cells ............. 149
7.13 Mesenchymal Stem Cells Are Located Throughout the
Body ................................................ 150
8 Redox Signaling ........................................... 155
8.1 Hydrogen Peroxide and Nitric Oxide Are Signaling
Molecules ........................................... 156
8.2 Nox Enzymes ......................................... 157
8.3 Oxidation of Sulfhydryls and Hydrogen Peroxide
Signaling ........................................... 159
8.4 Nitric Oxide Synthases and Nitric Oxide Signaling ... 162
8.5 The Frank-Starlings Law and Excitation-Contraction
Coupling ............................................ 164
8.6 Transcriptional Regulation of the Metabolic
Programs ............................................ 166
8.7 Inappropriate S-Nitrosylation Contributes to
Neurodegenerative Disorders ......................... 168
8.8 The Electron Transport Chain Can Generate Reactive
Oxygen Species ...................................... 170
Further Reading ........................................... 172
Part II Cancer
9 The Cell Cycle ............................................ 179
9.1 The Cell Cycle Has Four Phases ...................... 182
9.2 Ubiquitin-Mediated Proteolysis Is a Key Part of
the Cell Cycle Machinery ............................ 183
9.3 Several Families of Activators and Inhibitors Are
Part of the Cell Cycle Engine ....................... 184
9.4 The Retinoblastoma Proteins and E2F Transcription
Factors Are Downstream Cell Cycle Effectors at the
Gl/S Transition ..................................... 185
9.5 Cell Cycle Effectors at the G2/M Transition ......... 187
9.6 The SCF and APC/C Are Large Multisubunit
Complexes ........................................... 188
9.7 Mathematical Modeling Is an Essential Tool in
Understanding Signaling Pathways and Networks ....... 189
9.8 The Goldbeter Model of Entry and Exit from
Mitosis ............................................. 192
9.9 Multiple Positive and Negative Feedback Regulate
the Progression Through the Cell Cycle .............. 194
9.10 Multisite Phosphorylation Helps Ensure the Correct
Ordering of Events .................................. 196
9.11 Traversing the Cell Cycle with the APC and SCF ...... 196
Further Reading ........................................... 197
10 Cell Cycle Checkpoints and DNA Damage Repair .............. 201
10.1 The G1/S Checkpoint Pathway ......................... 202
10.2 Formation of IRIFs and Activation of ATM ............ 203
10.3 Mediators Amplify the ATM Signal .................... 205
10.4 Intra-S Phase and G2/M Checkpoints .................. 206
10.5 Formation of SDSCs and Activation of ATR ............ 207
10.6 Structure and Posttranslational Modifications of
Checkpoint Proteins ................................. 208
10.7 p53 Structure and Function .......................... 210
10.8 Restoration of p53 Function by Second-Site
Suppressors ......................................... 212
10.9 Special Domains Mediate Protein-Protein
Interactions and Chromatin Binding by Proteins
that Function at the Apex of the Checkpoint and
Repair Pathways ..................................... 213
10.10 Base Excision Repair ................................ 214
10.11 Nucleotide Excision Repair .......................... 216
10.12 Mismatch Repair ..................................... 216
10.13 Repair Proteins Diffuse Laterally in One-Dimension
Along DNA ........................................... 217
10.14 There Are Two Double-StrandBreak Repair Systems ..... 218
10.15 The Mre11-Rad50-Nbs1 (MRN) Complex Is Involved in
DNA Damage Sensing, Signaling, and Repair ........... 220
10.16 Completing the Repair and Terminating the
Checkpoint .......................................... 221
Further Reading ........................................... 222
11 Apoptosis and Senescence .................................. 227
11.1 Pathways to Apoptosis - Extrinsic and Intrinsic ..... 228
11.2 Bcl2 Proteins Mediate the Apoptotic Balance ......... 230
11.3 Sequestration and Release of Cytochrome с ........... 232
11.4 Damage-Induced Apoptosis via p53 Transcription
and Mitochondrial Actions ........................... 233
11.5 Cells That Are Healthy Do Not Have an Unlimited
Capacity to Divide .................................. 234
11.6 Telomere Structure and Capping Proteins ............. 234
11.7 Cancer Cells Increase Their Production of
Telomerase, an Enzyme That Immortalizes the Cells ... 235
11.8 Regulation of Replicative Senescence by p53 and
pRb ................................................. 236
11.9 DNA Damage and Oncogene-Induced Senescence .......... 237
11.10 A Model or Two of Oncogene-Induced Stress ........... 238
11.11 p53 Undergoes Posttranslational Modifications
Including Phosphorylation, Acetylation, and
Ubiquitination at Multiple Sites .................... 240
11.12 Heterochromatin Formation Provides a Route to
Oncogene-Induced Senescence ......................... 241
11.13 The Retinoblastoma Protein Helps Establish the
Senescent State by Mediating Heterochromatin
Formation ........................................... 243
Further Reading ........................................... 244
12 Epigenetics ............................................... 249
12.1 Nucleosomes and Chromatin Structure ................. 250
12.2 Epigenetic Marks .................................... 251
12.3 DNA Methylation ..................................... 253
12.4 Polycomb and Trithorax Group Proteins ............... 254
12.5 Histone Acetylation and Deacetylation ............... 254
12.6 Histone Methylation and Demethylation ............... 255
12.7 Reading Out Histone Marks by Recognition Modules .... 256
12.8 Cooperative Actions by Histone Modification
Enzymes and DNA Methyltransferases Can Silence
Genes and Lead to Cancer ............................ 259
12.9 Recently Discovered Small Noncoding RNAs (ncRNAs)
Regulate Gene Expression ............................ 260
12.10 Atomic-Level Studies of Dicer and Sheer Provide
Crucial Insights into ncRNA Function ................ 262
12.11 MicroRNAs and Cancer ................................ 264
12.12 Induced Pluripotent Stem Cells ...................... 266
Further Reading ........................................... 267
13 Tumor Growth .............................................. 271
13.1 Growth and Survival Signaling Pathways .............. 271
13.2 Receptor Activation Leads to Recruitment of
Molecular Adaptors to Docking Sites ................. 273
13.3 Ras and Other Small GTPases Link Adaptors to
Downstream Signaling Elements ....................... 275
13.4 Many of the Growth Signaling Proteins Function as
Oncogenes ........................................... 276
13.5 MAP Kinase Signaling Modules ........................ 278
13.6 The MAP Kinase Modules and Their Substrates
Function as Dynamical Circuits ...................... 280
13.7 Active and Inactive Conformations of Protein
Kinases ............................................. 281
13.8 Oncogene Addiction .................................. 282
13.9 Target-Based Anticancer Therapies ................... 283
13.10 Мус Protein Structure and Function .................. 284
13.11 Phosphorylation and Polyubiquitination Sculpt
Мус-Mediated Gene Transcription ..................... 285
13.12 Regulation of Cellular Growth by Ras, Erk, and
Мус ................................................. 286
13.13 Regulation of Cellular Proliferation by Мус ......... 287
Further Reading ........................................... 288
14 Tumor Metabolism .......................................... 291
14.1 The Central Growth Network of the Cell Is
Organized About the mTOR Cassette ................... 292
14.2 AMPK Supplies a Gating Signal Indicative of Energy
Balance ............................................. 293
14.3 Cells Halt Growth in Response to Hypoxia and Other
Cellular Stresses ................................... 293
14.4 Regulation of Cell Growth by Amino Acid Starvation
Signaling to mTOR ................................... 295
14.5 Regulation of the Translation Initiation Complex
by mTOR ............................................. 296
14.6 Starvation and Autophagy ............................ 298
14.7 p53 Modulation of Metabolism Is One of Its Barrier
Functions ........................................... 300
14.8 The PTEN Tumor Suppressor Acts at the Plasma
Membrane and in the Nucleus ......................... 302
14.9 Mutations and Disturbed Redox Balance Deactivate
PTEN ................................................ 303
14.10 HIF Transcription Factors Sense and Respond to
Low Oxygen Conditions ............................... 304
14.11 HIFs Regulate Cellular Metabolism and Drive the
Glycolytic Shift .................................... 306
14.12 Hexokinase II and Akt Drive the Glycolytic Shift
and Prevent Apoptosis in Tumors ..................... 307
Further Reading ........................................... 309
15 Metastasis ................................................ 313
15.1 Tumor Growth and Metastasis Are Community Affairs ... 314
15.2 Macrophages and Fibroblasts Direct Invasion and
Intravasation ....................................... 316
15.3 The SDF-1 /CXCR4 Axis Is a Central Participant in
Metastasis .......................................... 317
15.4 Focal Adhesions and Metastasic Migration ............ 318
15.5 Receptor Cooperativity and Src Signaling ............ 320
15.6 The Transforming Growth Factor-β Pathway ............ 322
15.7 TGF-β Promotes Cytostasis ........................... 325
15.8 The Wnt Pathway ..................................... 326
15.9 The Epithelial to Mesenchymal Transition ............ 327
15.10 MicroRNAs and Transcription Repressors Jointly
Regulate E-Cadherin Expression ...................... 329
15.11 MicroRNAs Act as Metastasis Repressors and
Activators .......................................... 331
15.12 Stem Cells and Cancer Stem Cells .................... 331
15.13 Changing Views About Metastatic Spread .............. 332
15.14 The Notch Pathway ................................... 333
15.15 The Hedgehog Pathway in Drosophila .................. 335
15.16 The Hedgehog Pathway in Mammals ..................... 336
15.17 Bone Metastasis Is a Seed-and-Soil Exemplar ......... 338
Further Reading ........................................... 339
Part III Neurodegeneration
16 Protein Folding, Misfolding, and Aggregation .............. 345
16.1 Proteins Spontaneously Fold into Their Native
State Based Solely on Their Primary Amino Acid
Sequence ............................................ 348
16.2 Protein Folding Can Be Described in Terms of an
Energy Landscape Dominated by a Folding Funnel ...... 349
16.3 Some Landscapes Are Smooth While Others Are
Rugged .............................................. 351
16.4 Proteins, Especially Those Involved in Signaling,
Often Fold into Nonglobular, Extended
Conformations ....................................... 352
16.5 Dialysis-Related Amyloidosis Is Brought on by
Partial Unfolding and Aggregation of β-2
Microglobulin ....................................... 354
16.6 β Cell Failure and Amyloid Formation in Type 2
Diabetes Is Brought on by Amylin Misfolding and
Aggregation ......................................... 357
16.7 Some Proteins Have Native States That Are
Metastable and Not at a Global Minimum in the Free
Energy .............................................. 357
16.8 β-Sheet Conformational Variations Underlie the
Prion Strains and Disease Potential ................. 358
16.9 Strains and Transmissibility ........................ 361
16.10 General Observations on How Proteins Fold into
Alternative Disease-Causing Structures
Characterized by Cross-β-Sheets ..................... 362
Further Reading ........................................... 364
17 Alzheimer's Disease ....................................... 369
17.1 Generation of the Amyloid β Protein ................. 370
17.2 Removal Through Degradation and Clearance ........... 373
17.3 Folding Physics, Metal Homeostasis, and Redox
Chemistry ........................................... 375
17.4 Normal Physiological Function of the Aβ Protein
at the Synapse ...................................... 376
17.5 Action of the Aβ Oligomers at the Synapse -
Aberrant LTD ........................................ 377
17.6 The Local Microenvironment Contains Neurons,
Astrocytes, and Microglia ........................... 379
17.7 Microglia Respond to Amyloid Plaque Buildup by
Mounting an Inflammatory Response ................... 380
17.8 Inflammatory and Synaptic Cytokines Are Released
by Microglia and Astrocytes ......................... 382
17.9 Tau Hyperphosphorylation and Formation of the
Tangles ............................................. 384
Further Reading ........................................... 387
18 Chaperones, Endoplasmic Reticulum Stress, and the
Unfolded Protein Response ................................. 391
18.1 The Cellular Complement of Molecular Chaperones ..... 392
18.2 Hsp70 Structure and Function ........................ 393
18.3 Hsp90 Structure and Function ........................ 394
18.4 Heat Shock Factor 1 Is a Master Regulator of
Protein Homeostasis ................................. 396
18.5 Folding, Processing, and Maturation of Membrane
and Secreted Proteins ............................... 397
18.6 N-Linked Glycan Processing .......................... 399
18.7 The Unfolded Protein Response ....................... 401
18.8 ERAD and the Sec61 Translocon ....................... 404
18.9 The p97 Motor Protein Is a Molecular Chaperone
Required for ERAD ................................... 405
Further Reading ........................................... 407
19 Parkinson's Disease ....................................... 411
19.1 α-Synuclein Is a Presynaptic Protein ................ 414
19.2 Abnormalities and Toxicity Result from α-Synuclein
Misfolding and Aggregation .......................... 414
19.3 Oxidative Damage Is a Cause of α-Synuclein
Aggregation and PD .................................. 415
19.4 Parkin Is an E3 Ubiquitin Ligase .................... 416
19.5 Protein Carbonylation and UCH-L1 .................... 417
19.6 PINK1 Is a Neuroprotective Serine/Threonine
Kinase .............................................. 417
19.7 DJ-1 Protects Against Oxidative Stress .............. 418
19.8 LRRK2 Is a ROCO Family Member and Mutations in
This Protein Are Most Strongly Associated with PD ... 419
19.9 HtrA2/Omi Removes Misfolded Proteins ................ 420
19.10 The Pathway Is Illuminated .......................... 421
19.11 Proteasome Organization ............................. 422
19.12 Cellular Garbage Collection and the Aggresomal-
Autophagic Railway .................................. 424
19.13 Histone Deacetylase 6 Mediates Transport Along
the Disposal Railway ................................ 425
Further Reading ........................................... 426
20 Huntington's Disease and Amyotrophic Lateral Sclerosis .... 431
20.1 Huntington's Disease Is an Expanded PolyQ Repeat
Disorder ............................................ 432
20.2 The Structure of the Huntingtin Protein Is That of
a Multipurpose Signaling Organizer .................. 434
20.3 Synaptic Terminal Interactions Occur ................ 434
20.4 Impaired Fast Axonal Transport Happens .............. 436
20.5 Zippers, Aggregation, Fibrils, Inclusion Body
Formation, and Toxicity ............................. 436
20.6 The Ubiquitin-Proteasome System Regulates Synaptic
Transmission and This Function Is Impaired by
Mutant Htt .......................................... 438
20.7 Impaired Transcription: СВР and PGC-1 - and
Mitochondrial Dysfunction ........................... 439
20.8 Structure and Folding of the Superoxide Dismutase
Protein SOD1 ........................................ 440
20.9 SOD1 Mutations and Aggregation ...................... 441
20.10 Impaired Fast Axonal Transport and Retraction of
Axons from Synapses ................................. 442
20.11 A Model for Amyotrophic Lateral Sclerosis ........... 443
20.12 Acceleration of ALS Through Interactions Between
Neurons and Other Cellular Residents of Its
Microenvironment .................................... 444
20.13 PolyQs, Mutant SOD1, and Impaired ERAD .............. 446
20.14 Mutations in Genes Other Than That for SOD1 Can
Cause fALS .......................................... 447
20.15 Interlocking Signaling Networks Underlie Health
and Disease ......................................... 449
Further Reading ........................................... 450
Index ......................................................... 455
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