1 Basics of Cell Signaling ..................................... 1
1.1 Cell Signaling: Why, When and Where? .................... 1
1.2 Intercellular Signaling ................................. 3
1.2.1 Tools for Intercellular Signaling ................ 3
1.2.2 Steps of Intercellular Signaling ................. 5
1.2.3 Regulation of Intercellular Signaling ............ 7
1.3 Hormones in Intercellular Signaling ..................... 8
1.3.1 Chemical Nature of Hormones ...................... 8
1.3.2 Hormone Analogs: Agonists and Antagonists ....... 12
1.3.3 Endocrine, Paracrine and Autocrine Signaling .... 13
1.3.4 Direct Protein Modification by Signaling
Molecules ....................................... 15
1.4 Intracellular Signaling: Basics ........................ 15
1.4.1 Reception of External Signals ................... 15
1.4.2 Activation and Deactivation of Signaling
Proteins ........................................ 16
1.4.3 Processing of Multiple Signals .................. 17
1.4.4 Variability of Signaling Proteins ............... 17
1.5 Molecular Tools for Intracellular Signaling ............ 18
1.5.1 Receptors ....................................... 18
1.5.2 Signaling Enzymes ............................... 21
1.5.3 Adaptors and Scaffolding Proteins ............... 22
1.5.4 Diffusible Intracellular Messengers: Second
Messengers ...................................... 22
1.6 Basic Mechanisms of Intracellular Signaling ............ 24
1.6.1 Regulatory Modifications ........................ 24
1.6.2 Recognition of Protein Modifications by
Modification-specific Protein Modules ........... 25
1.6.3 Multisite Protein Modification .................. 26
1.6.4 Protein Interaction Domains ..................... 28
1.7 Modular Structure of Signaling Proteins and
Signaling Complexes .................................... 32
1.7.1 Modules in Signaling Proteins ................... 32
1.7.2 Modular Signaling Complexes ..................... 33
1.8 Organization of Signaling .............................. 34
1.8.1 Linear Signaling Pathways, Branching and
Crosstalk ....................................... 35
1.8.1.1 Linear Pathways ........................ 35
1.8.1.2 Branching and Crosstalk ................ 37
1.8.1.3 Interactions between Signaling Paths ... 37
1.8.2 Signaling Networks .............................. 38
1.8.2.1 Complexity of Signaling Networks ....... 39
1.8.2.2 Properties of Signaling Networks ....... 39
1.8.2.3 Nodes and Junctions .................... 41
1.8.2.4 Feedback Loops ......................... 42
1.8.3 Redundancy and Specificity of Signaling ......... 46
1.8.4 Regulation of Signaling Pathways ................ 47
1.8.5 Spatial Organization of Signaling Pathways ...... 49
1.8.6 Compartmentalization and Transport .............. 50
1.8.7 Evolution of Signaling Pathways ................. 51
1.9 Variability and Cell-type Specificity of Signaling ..... 51
1.10 References ........................................ 53
2 Regulation of Enzyme Activity ............................... 55
2.1 Basis of Enzyme Catalysis .............................. 56
2.2 Basics of Allosteric Regulation ........................ 58
2.3 Regulation of Enzymes by Effector Molecules ............ 60
2.4 Regulation of Enzyme Activity by Phosphorylation ....... 62
2.5 "Ubiquitin (Ub)-Proteasome" Pathway .................... 64
2.5.1 Components of the Ub System ..................... 65
2.5.2 Ub and Ub-like Proteins ......................... 66
2.5.3 Activation and Transacylation of Ub: El and
E2 Enzymes ...................................... 67
2.5.4 Transfer to the Target Protein with the
Participation of E3 ............................. 69
2.5.5 HECT Domain E3 Enzymes .......................... 71
2.5.6 RING Domain E3 Enzymes .......................... 72
2.5.6.1 N-end Rule Enzymes ..................... 73
2.5.6.2 Cbl Protein ............................ 73
2.5.6.3 Cullin-based E3 Enzymes, SCF and APC ... 74
2.5.6.4 Processing of Nuclear Factor (NF) кВ
and Degradation of IkB ................. 76
2.5.7 Degradation in the Proteasome ................... 78
2.5.8 Other Regulatory Functions of Ub Conjugation .... 80
2.5.9 Regulation of Proteins by Sumoylation ........... 82
2.6 Lipidation of Signaling Proteins ....................... 83
2.6.1 Myristoylation .................................. 84
2.6.2 Palmitoylation .................................. 85
2.6.3 Farnesylation and Geranylation .................. 86
2.6.4 Dual Lipidation ................................. 87
2.6.5 Cholesterol Membrane Anchor ..................... 88
2.6.6 Switch Function of Lipid Anchors ................ 88
2.6.7 Glycosylphosphatidylinositol (GPI) Anchor ....... 90
2.7 References ............................................. 91
3 Regulation of Gene Expression ............................... 93
3.1 Basic Steps of Gene Expression ......................... 93
3.2 Components of the Eukaryotic Transcription Machinery ... 95
3.2.1 Basic Features of Eukaryotic Transcription ...... 96
3.2.2 Elementary Steps of Eukaryotic Transcription .... 98
3.2.3 Eukaryotic RNA Polymerases ...................... 98
3.2.4 Structure of the Transcription Start Site and
Regulatory Sequences ........................... 100
3.2.5 General Transcription Factors and the Core
Transcription Apparatus ........................ 101
3.2.6 Holoenzyme Forms of RNA Pol II ................. 103
3.2.7 Phosphorylation of RNA Pol II and the Onset
of Transcription ............................... 104
3.2.8 TFIIH - A Pivotal Regulatory Protein Complex ... 106
3.2.9 Mediator Complex ............................... 107
3.3 Principles of Transcription Regulation ................ 109
3.3.1 Elements of Transcription Regulation ........... 109
3.3.2 Regulation of Eukaryotic Transcription by
Sequence-specific DNA-binding Proteins ......... 111
3.3.3 DNA Binding of Transcriptional Regulators ...... 112
3.3.4 Structure of the Recognition Sequence and
Quaternary Structure of DNA-binding Proteins ... 113
3.3.5 Communication with the Transcription
Apparatus: Transactivation Domains ............. 115
3.3.6 Families of Sequence-specific Transcription
Factors and Homo- or Heterodimerization ........ 116
3.4 Control of Transcription Factors ...................... 118
3.4.1 Mechanisms for the Control of Regulatory
DNA-binding Proteins ........................... 118
3.4.2 Changes in the Concentration of Regulatory
DNA-binding Proteins ........................... 119
3.4.3 Regulation by Binding of Effector Molecules .... 119
3.4.4 Posttranslational Modification of
Transcription Regulators ....................... 120
3.4.5 Regulation by Phosphorylation .................. 121
3.4.6 Regulation by Methylation, Acetylation and
Redox Modification ............................. 125
3.4.7 Transcriptional Regulation in the Framework
of Signal Transduction Networks ................ 125
3.4.7.1 Constitutively Active Transcription
Factors ............................... 126
3.4.7.2 Regulatory Transcription Factors ...... 126
3.4.8 Repression of Transcription .................... 128
3.4.9 Coregulators of Transcription .................. 130
3.5 Chromatin Structure and Transcription Regulation ...... 131
3.5.1 Nucleosome and Chromatin Structure ............. 132
3.5.2 Histone Acetylation and Deacetylation .......... 134
3.5.3 Histone Methylation ............................ 136
3.5.3.1 Histone Arginine Methylation .......... 136
3.5.3.2 Arginine Demethylation/
Citrullination ........................ 138
3.5.3.3 Histone Lysine Methylation ............ 138
3.5.3.4 Histone Lysine Demethylation .......... 139
3.5.4 Histone Phosphorylation ........................ 140
3.5.5 Histone Ubiquitination and Sumoylation ......... 141
3.5.6 Histone Modification "Code" .................... 141
3.5.7 Recognition of Histone Modifications by
Protein Domains ................................ 143
3.5.8 DNA Methylation ................................ 144
3.5.9 Summary of the Regulatory Steps in
Transcription .................................. 148
3.6 Posttranscriptional Regulation of Gene Expression ..... 150
3.6.1 Control at the Level of Pre-mRNA Processing .... 151
3.6.2 Stability of mRNA .............................. 155
3.6.3 Regulation at the Level of Translation ......... 157
3.6.3.1 General Mechanisms of Translational
Control ............................... 157
3.6.3.2 mRNA-specific Regulation by 5'
Sequences: Control of Ferritin mRNA
Translation by Iron ................... 159
3.6.3.3 mRNA-specific Translational
Regulation by Protein Binding to
3'-Untranslated Regions ............... 160
3.6.3.4 Global Translational Regulation of
mRNAs by Targeting eIF-4E ............. 162
3.6.3.5 Regulation of Translation via elF-2 ... 164
3.7 Regulation by RNA Interference (RNAi) ................. 167
3.7.1 Small Regulatory RNAs .......................... 170
3.7.2 Incorporation of Small RNAs into RISC .......... 172
3.7.3 Cleaving the Target RNA ........................ 173
3.7.4 Specificity and Target Selection in RNAi ....... 175
3.7.5 Biological Functions of RNAi ................... 176
3.7.5.1 Functions and Applications of
siRNAs ................................ 176
3.7.5.2 Functions of miRNAs ................... 176
3.7.5.3 RISCs and Chromatin Structure ......... 177
3.8 References ............................................ 179
4 Signaling by Nuclear Receptors ............................. 181
4.1 Ligands of Nuclear Receptors .......................... 181
4.2 Principles of Signaling by Nuclear Receptors .......... 184
4.3 Classification and Structure of Nuclear Receptors ..... 186
4.3.1 DNA-binding Elements of Nuclear Receptors:
HREs ........................................... 187
4.3.2 The DNA-binding Domain of Nuclear Receptors .... 189
4.3.3 HRE Recognition and Structure of the HRE-
Receptor Complex ............................... 190
4.3.4 Ligand-binding Domain (LBD) .................... 191
4.3.5 Transactivating Elements of the Nuclear
Receptors ...................................... 195
4.4 Mechanisms of Transcriptional Regulation by
Nuclear Receptors ..................................... 196
4.4.1 Steroid Receptor Coactivator (SRC)-l/pl60
and Thyroid Hormone Receptor-activating
Protein (TRAP) Coactivators .................... 198
4.4.2 Corepressors of Nuclear Receptors .............. 200
4.5 Regulation of Signaling by Nuclear Receptors .......... 200
4.6 The Signaling Pathway of the Steroid Hormone
Receptors ............................................. 203
4.7 Signaling by Retinoids, Vitamin D3 and the T3
Hormone ............................................... 205
4.8 Nongenomic Functions of Nuclear Receptors and their
Ligands ............................................... 207
4.9 References ............................................ 211
5 G-protein-coupled Signal Transmission Pathways ............. 213
5.1 Transmembrane (TM) Receptors: General Structure and
Classification ........................................ 213
5.2 Structural Principles of TM Receptors ................. 215
5.2.1 The Extracellular Domain of TM Receptors ....... 217
5.2.2 TM Domain ...................................... 217
5.2.3 Intracellular Domain of Membrane Receptors ..... 219
5.2.4 Regulation of Receptor Activity ................ 221
5.3 GPCRs ................................................. 222
5.3.1 Classification of GPCRs ........................ 223
5.3.2 Structure of GPCRs ............................. 225
5.3.3 Ligand Binding and Mechanism of Signal
Transmission ................................... 227
5.3.4 Regulation of GPCRs ............................ 228
5.3.5 Switching Off and Desensitization of 7TM
Receptors ...................................... 229
5.3.6 Dimerization of GPCRs .......................... 233
5.4 Regulatory GTPases .................................... 233
5.4.1 The GTPase Superfamily General Functions and
Mechanism ...................................... 234
5.4.2 Inhibition of GTPases by GTP Analogs ........... 236
5.4.3 The G-domain as a Common Structural Element
of the GTPases ................................. 237
5.4.4 GTPase Families ................................ 238
5.5 Heterotrimeric G-proteins ............................. 239
5.5.1 Classification of the Heterotrimeric
G-proteins ..................................... 240
5.5.2 Toxins as Tools in the Characterization of
Heterotrimeric G-proteins ...................... 243
5.5.3 Functional Cycle of Heterotrimeric
G-proteins ..................................... 244
5.5.4 Structural and Mechanistic Aspects of the
Switch Function of G-proteins .................. 247
5.5.5 Structure and Function of the py-Complex ....... 253
5.5.6 Membrane Association of the G-proteins ......... 255
5.5.7 Regulators of G-proteins: Phosducin and RGS
Proteins ....................................... 256
5.6 Receptor-independent Functions of Heterotrimeric
G-proteins ............................................ 259
5.7 Effector Molecules of G-proteins ...................... 259
5.7.1 Adenylyl Cyclase and cAMP as "Second
Messenger" ..................................... 260
5.7.2 PLC ............................................ 264
5.8 GPCR Signaling via Arrestin ........................... 268
5.9 References ............................................ 269
6 Intracellular Messenger Substances: "Second Messengers" .... 271
6.1 General Properties of Intracellular Messenger
Substances ............................................ 272
6.2 cAMP .................................................. 273
6.3 cGMP and Guanylyl Cyclases ............................ 275
6.3.1 Guanylyl Cyclases .............................. 276
6.3.2 Targets of cGMP ................................ 277
6.4 Metabolism of Inositol Phospholipids and Inositol
Phosphates ............................................ 278
6.5 Storage and Release of Ca2+ ........................... 282
6.5.1 Release of Ca2+ from Ca2+ Storage .............. 282
6.5.2 Influx of Ca2+from the Extracellular Region .... 288
6.5.3 Removal and Storage of Ca2+ .................... 288
6.5.4 Temporal and Spatial Changes in Ca2+
Concentration .................................. 289
6.6 Functions of Phosphoinositides ........................ 290
6.6.1 Messenger Function of PtdIns(3,4,5)P3 .......... 291
6.6.2 Functions of PtdIns(4,5)P2 and other
Phosphoinositides .............................. 291
6.7 Ca2+ as a Signal Molecule ............................. 292
6.7.1 Calmodulin as a Ca2+ Sensor .................... 295
6.7.2 Target Proteins of Ca2+/Calmodulin ............. 297
6.7.3 Other Ca2+ Sensors ............................. 298
6.8 DAG as a Signal Molecule .............................. 299
6.9 Other Lipid Messengers ................................ 300
6.10 NO Signaling Molecule ................................. 301
6.10.1 Reactivity of NO ............................... 302
6.10.2 Synthesis of NO ................................ 303
6.10.3 Physiological Functions of Nitrosylation ....... 305
6.10.3.1 Nitrosylation of Metal Centers ........ 305
6.10.3.2 Regulatory Functions of
S-Nitrosylation ....................... 307
6.10.3.3 Toxic Action of NO and Nitrosative
Stress ................................ 309
6.11 References ............................................ 310
7 Ser/Thr-specific Protein Kinases and Protein
Phosphatases ............................................... 313
7.1 Classification, Structure and Characteristics of
Protein Kinases ....................................... 313
7.1.1 General Classification and Function of
Protein Kinases ................................ 313
7.1.2 Classification of Ser/Thr-specific Protein
Kinases ........................................ 315
7.2 Structure and Regulation of Protein Kinases ........... 316
7.2.1 Main Structural Elements of Protein Kinases .... 318
7.2.2 Substrate Binding and Recognition .............. 321
7.2.3 Control of Protein Kinase Activity ............. 322
7.2.4 Regulation of Protein Phosphorylation by
Subcellular Localization and Specific
Targeting Subunits ............................. 325
7.3 PKA ................................................... 327
7.3.1 Structure and Substrate Specificity of PKA ..... 327
7.3.2 Regulation of PKA .............................. 329
7.3.3 AKAPs .......................................... 330
7.4 Phosphatidylinositol-3-kinase (PI3K)/Akt Pathway ...... 332
7.4.1 PI3K ........................................... 332
1A1 PKB/Akt Kinase ........................................ 335
7.5 PKC ................................................... 338
7.5.1 Classification and Structure ................... 338
7.5.2 Activation of PKC by Cofactors ................. 341
7.5.3 Regulation of PKC .............................. 341
7.5.4 Receptors for PKC and RACK (Receptors for
Activated PKC) Proteins ........................ 344
7.5.5 Functions and Substrates of PKC ................ 345
7.6 Ca2+/Calmodulin-dependent Protein Kinases (CaMKs) ..... 346
7.6.1 Importance and General Function ................ 346
7.6.2 CaMK II ........................................ 347
7.7 Ser/Thr-specific Protein Phosphatases ................. 351
7.7.1 Structure and Classification of Ser/Thr
Protein Phosphatases ........................... 351
7.7.2 Regulation of Ser/Thr Protein Phosphatases ..... 352
7.7.3 PP1 ............................................ 353
7.7.4 PP2A ........................................... 354
7.7.5 PP2B (Calcineurin) ............................. 356
7.8 References ............................................ 359
8 Signal Transmission via Transmembrane Receptors
with Tyrosine-Specific Protein Kinase Activity ............. 361
8.1 Structure and Function of RTKs ........................ 363
8.1.1 General Structure and Classification ........... 363
8.1.2 Ligand Binding and Receptor Dimerization ....... 365
8.1.3 Structure and Activation of the Tyrosine
Kinase Domain .................................. 369
8.1.4 Effector Proteins of the RTKs .................. 373
8.1.5 Attenuation and Termination of RTK Signaling ... 376
8.2 Protein Modules in Downstream Signaling of RTKs ....... 379
8.2.1 Domains with Binding Specificity for
Phosphotyrosine: SH2, PTB and C2 Domains ....... 381
8.2.2 SH3 Domains .................................... 384
8.2.3 Membrane-targeting Domains: Pleckstrin
Homology (PH) Domains and FYVE Domains ......... 385
8.2.4 Phosphoserine/Threonine-binding Domains ........ 386
8.2.5 PDZ Domains .................................... 387
8.3 Non-RTK-specific Protein Kinases ...................... 388
8.3.1 Structure and General Function of Non-RTKs ..... 389
8.3.2 Src Tyrosine Kinase ............................ 390
8.3.3 Abl Tyrosine Kinase ............................ 392
8.4 PTPs .................................................. 395
8.4.1 Structure and Classification of PTPs ........... 396
8.4.2 Cooperation of PTPs and Protein Tyrosine
Kinases ........................................ 399
8.4.3 Regulation of PTPs ............................. 401
8.5 Adaptor Molecules of RTKs ............................. 404
8.6 References ............................................ 408
9 Signal Transmission via Ras Proteins ....................... 411
9.1 Ras Superfamily of Monomeric GTPases .................. 411
9.2 GAPs of the Monomeric GTPases ......................... 413
9.3 GEFs of the Monomeric GTPases ......................... 414
9.4 Inhibitors of G-nucleotide dissociation GDIs .......... 416
9.5 Ras Family of Monomeric GTPases ....................... 417
9.5.1 General Properties of the Ras Protein .......... 418
9.5.2 Structure of the GTP- and GDP-bound Forms of
Ras Protein .................................... 419
9.5.3 GTP Hydrolysis Mechanism and Stimulation by
GAP Proteins ................................... 420
9.5.4 Structure and Biochemical Properties of
Transforming Mutants of Ras Protein ............ 422
9.5.5 Membrane Localization of Ras Protein ........... 423
9.5.6 GAPs in Ras Signal Transduction ................ 424
9.5.7 GEFs in Ras Signal Transduction ................ 424
9.6 Raf Kinase as an Effector of Signal Transduction by
Ras Proteins .......................................... 427
9.6.1 Structure of Raf Kinase ........................ 427
9.6.2 Mechanism of Activation and Regulation of Raf
Kinase ......................................... 428
9.6.3 Oncogenic Activation of Raf .................... 430
9.7 Further Ras Family Members: R-Ras, Ral and Rap ........ 430
9.8 Reception and Transmission of Multiple Signals by
Ras Protein ........................................... 431
9.8.1 Multiple Input Signals of Ras Protein .......... 431
9.8.2 Multiple Effector Molecules of Ras Proteins .... 432
9.9 Further Branches of the Ras Superfamily ............... 434
9.9.1 Rho/Rac Family ................................. 434
9.9.2 Rab Family ..................................... 435
9.9.3 Ran Family ..................................... 435
9.9.4 Arf Family ..................................... 436
9.10 Ras Protein Network and Crosstalk within the Ras
Superfamily ........................................... 436
9.11 References ............................................ 439
10 Intracellular Signal Transduction: Protein Cascades of
the Mitogen-activated Protein Kinase Pathways .............. 441
10.1 Organization and Components of МАРК Pathways .......... 443
10.2 Regulation of МАРК Pathways by Protein Phosphatases
and Inhibitory Proteins ............................... 446
10.3 Specificity in МАРК Activation and Organization in
Multiprotein Complexes ................................ 447
10.4 Major МАРК Pathways of Mammals ........................ 450
10.4.1 ERK Pathway .................................... 450
10.4.2 JNK and p38 МАРК Pathways ...................... 451
10.5 References ............................................ 456
11 Membrane Receptors with Associated Tyrosine
Kinase Activity ............................................ 457
11.1 Cytokines and Cytokine Receptors ...................... 457
11.2 Structure and Activation of Cytokine Receptors ........ 458
11.2.1 Activation of Cytoplasmic Tyrosine Kinases ..... 465
11.2.2 The JAK-STAT Pathway ........................... 468
11.2.2.1 JAKs .................................. 468
11.2.2.2 STAT Proteins ......................... 469
11.2.3 Regulation of Cytokine Receptor Signaling ...... 472
11.3 T and В Cell Receptors (TCRs and BCRs) ................ 474
11.3.1 Receptor Structure ............................. 474
11.3.2 Intracellular Signal Molecules of the TCRs
and BCRs ....................................... 476
11.4 Signal Transduction via Integrins ..................... 478
11.5 References ............................................ 482
12 Other Transmembrane Receptor Classes ....................... 483
12.1 Receptors with Intrinsic Ser/Thr Kinase Activity:
TGF-β Receptor and SMAD Protein Signaling ................. 484
12.1.1 Family of TGF-β Cytokines ...................... 484
12.1.2 TGF-β Receptor ................................ 485
12.1.3 SMAD Proteins .................................. 486
12.2 Receptor Regulation by Intramembrane Proteolysis:
Notch Receptor ........................................ 491
12.3 References ............................................ 494
13 Regulation of the Cell Cycle ............................... 495
13.1 Principles of Cell Cycle Control ...................... 496
13.2 Key Elements of the Cell Cycle Apparatus .............. 499
13.2.1 CDKs ........................................... 499
13.2.2 Cyclins ........................................ 502
13.2.3 CKIs ........................................... 505
13.3 CDK-Cyclin Complexes .................................. 507
13.3.1 Structure of CDKs and CDK-Cyclin complexes ..... 508
13.3.2 Regulation of CDKs by Phosphorylation .......... 509
13.3.3 Inhibition by CKIs ............................. 511
13.3.4 Substrates of С D Ks ........................... 512
13.3.5 Multiple Regulation of CDKs .................... 514
13.4 Regulation of the Cell Cycle by Proteolysis ........... 515
13.4.1 Proteolysis mediated by the SCF Complex ........ 516
13.4.2 Proteolysis mediated by the APC ................ 517
13.5 G1 Progression and S-phase Entry ...................... 518
13.5.1 CDK4/6 and the D-type Cyclins .................. 519
13.5.2 Central Function of CDK2-Cyclin E in S-phase
Entry .......................................... 521
13.5.3 Function of Rb in the Cell Cycle ............... 522
13.5.4 E2F Transcription Factors and their Control
by Rb .......................................... 523
13.5.5 Negative Regulation of the G1/S Transition ..... 526
13.6 Cell Cycle Control of DNA Replication ................. 527
13.7 The G2/M Transition and CDC25C Phosphatase ............ 529
13.8 Progression through the M phase: APC and the
Metaphase-Anaphase Transition ......................... 531
13.9 Summary of Cell Cycle Progression ..................... 533
13.10 DNA Damage and DNA Replication Checkpoints ........... 536
13.10.1 Components and Organization of DNA Damage
Checkpoints ................................... 537
13.10.2 Mammalian Ga DNA Damage Checkpoint ............ 539
13.10.3 S-phase Checkpoint Pathways ................... 540
13.10.4 G2/M Checkpoint ............................... 540
13.11 References ........................................... 541
14 Malfunction of Signaling Pathways and Tumorigenesis:
Oncogenes and Tumor Suppressor Genes ....................... 543
14.1 General Aspects of Tumor Formation .................... 543
14.1.1 Characteristics of Tumor Cells ................. 543
14.1.2 Genetic Changes in Tumor Cells ................. 545
14.1.3 Epigenetic Changes in Tumor Cells .............. 546
14.2 Signaling Proteins Mutated in Cancer:
Oncogenes ............................................. 548
14.2.1 Mechanisms of Oncogene Activation .............. 549
14.2.2 Examples of the Functions of Oncogenes ......... 552
14.3 Tumor Suppressor Genes: General Functions ............. 558
14.4 Rb in Cancer .......................................... 559
14.5 pl6INK4a Gene Locus and ARF ........................... 564
14.6 Tumor Suppressor Protein p53 .......................... 565
14.6.1 Structure and Biochemical Properties of p53 .... 565
14.6.2 Structure of p53 and its DNA Complex ........... 567
14.6.3 Posttranslational Modification of p53 .......... 567
14.6.4 Genes Regulated by p53 ......................... 570
14.6.5 Regulation of p53 by Ubiquitination and
Proteasomal Degradation: The MDM2 Protein ...... 573
14.6.6 Pathways Involved in Activation of p53 ......... 575
14.6.7 The MDM2-p53 Network and Cancer ................ 578
14.7 Wnt/(3-Catenin Signaling and the Tumor Suppressor
APC ................................................... 578
14.8 Genomic instability and Tumor Formation: Roles of
DNA Repair and DNA Damage Checkpoints ................. 580
14.9 Common Physiologic Changes in Tumor Cells: Hallmarks
of Cancer ............................................. 582
14.9.1 Self-sufficiency in Growth Signals ............. 583
14.9.2 Insensitivity to Antigrowth Signals ............ 584
14.9.3 Evasion of Programmed Cell Death (Apoptosis) ... 585
14.9.4 Limitless Replicative Potential of Cancer
Cells .......................................... 586
14.10 References ........................................... 587
15 Apoptosis .................................................. 589
15.1 Basic Functions of Apoptosis .......................... 589
15.2 Overview of Apoptotic Pathways ........................ 591
15.3 Caspases: Death by Proteolysis ........................ 592
15.3.1 Initiator and Effector Caspases ................ 593
15.3.2 Mechanism of Caspases .......................... 594
15.3.3 Caspase Activation and Regulation .............. 596
15.4 Bcl-2 Proteins Family: Gatekeepers of Apoptosis ....... 599
15.5 The Mitochondrial Pathway of Apoptosis ................ 602
15.6 Death Receptor-triggered Apoptosis .................... 606
15.6.1 Fas/CD95 Signaling Pathway ..................... 607
15.6.2 TNFR1 and Apoptosis ............................ 609
15.7 Links of Apoptosis to Cellular Signaling Pathways ..... 610
15.7.1 Phosphatidylinositol-3-kinase (PI3K)/Akt
Kinase and Apoptosis ........................... 611
15.7.2 p53 and Apoptosis .............................. 612
15.8 References ............................................ 615
Subject Index ................................................. 617
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