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Peptide Growth Factorsand Their Receptors IIContributors j \ N^6 -
J.EBattey, B.Beutler, L.Bonewald, R.L.Cate, M.VChao,P.K.Donahoe, K.Elgjo, J.Folkman, T.Graf, R.Grosse,M.E.Gurney, VK.M.Han, C.-H.Heldin, A.Hsueh, M.Klagsbrun,O.D.Laerum, P.Langen, A.-M.Lebacq-Verheyden, D.C.Lee,A.Leutz, L.A.Liotta, D.T.MacLaughlin, G.R.Martin,K.Miyazono, D.Monard, M.A.S.Moore, D.E.Mullins, G.R.Mundy,C.E Nathan, WR. Paukovits, WE. Paul, J.Pfeilschifter,D.B.Rifkin, C.Rivier, A.C.Sank, E.A.Sausville, E.Schiffmann,M.L.Stracke, J.Trepel, W.Vale, J.Vilcek, E.S.Vitetta,S.M.Wahl, H.L.Wong, J.Yu
Editors
Michael B. Sporn and Anita B. Roberts
Springer-VerlagBerlin Heidelberg New YorkLondon Paris TokyoHong Kong
Contents
Section B: Individual Growth Factors and Their Receptors(Cont'd from Part I)
CHAPTER 19
InterferonsJ. VILCEK. With 3 Figures 3
A. What Are Interferons? 3B. Structure of Interferon Genes and Proteins 4
I. Interferon-oc/j? (Type I IFN) 41. Human IFN-a/yS Genes and Proteins 52. IFN-a//? Genes and Proteins of Other Animal Species . . . 7
II. Interferon-y (Type II IFN) 7C. Interferon Induction and Production 9
I. Production of IFN-a/0 9II. Molecular Mechanisms of IFN-a/y? Induction 10
III. IFN-y Induction 11D. Interferon Receptors 12
I. IFN-a/0 Receptor • • • • 12II. IFN-y Receptor : . . . 13
E. Interferon Actions 15I. Molecular Mechanisms 15
1. Proteins Induced by the Interferons 152. Mechanisms of Gene Activation by Interferons 183. Common Mechanisms of Gene Activation by Interferons,
Viruses, Double-Stranded RNA, Growth Factors, andCytokines 19
II. Spectrum of Biological Activities 211. Inhibition of Cell Growth 212. Stimulation of Cell Growth 233. Other Biological Activities 244. Possible Physiological Roles 255. Roles in Pathophysiology and Therapeutic Applications . . 26
References 28
XII Contents
CHAPTER 20
Cachectin/Tumor Necrosis Factor and LymphotoxinB. BEUTLER. With 2 Figures 39
A. Introduction 39B. "Factor-Mediated" Diseases: The Hematopoietic Origin of Factors 40C. Cachectin 40D. Tumor Necrosis Factor 42E. Physical Structure of Cachectin/TNF: Homology to Lymphotoxin . 43F. Cachectin/TNF and Lymphotoxin: Production Sources, Kinetics,
and Stimuli 45G. Control of Cachectin Gene Expression 46H. Cachectin/TNF Receptor and Postreceptor Mechanisms 47J. Biological Effects of Cachectin/TNF and Lymphotoxin: In Vivo
and In Vitro 48I. Adipose Tissue 49
II. Muscle 49III. Liver 49IV. Gastrointestinal Tract 50V. Central Nervous System 50
VI. Adrenal 51VII. Skin 51
VIII. Bone and Cartilage 52IX. Vascular Endothelium 52X. Hematopoietic Elements . 53
1. Neutrophils 532. Eosinophils 543. Monocyte/Macrophages 544. Lymphocytes 55
K. Gross Physiologic and Pathologic Consequences of Cachectin/TNFProduction or Administration . . . 56
L. Disease States Associated with Elevated Levels of Cachectin/TNF . 57M. Cachectin/TNF and Its Clinical Applications: To Be or Not To Be 58References . 59
CHAPTER 21
Bombesin and Gastrin-Releasing Peptide: Neuropeptides, Secretogogues,and Growth FactorsA.-M. LEBACQ-VERHEYDEN, J. TREPEL, E. A. SAUSVILLE, and J. F. BATTEY.
With 3 Figures 71
A. Introduction 71B. Structure and Cellular Localization of the Peptides 71
I. Bombesin-Related Peptides 71II. Structure of Bombesin and GRP 72
Contents XIII
III. Molecular Forms of GRP 72IV. Cellular Localization of GRP 74
1. Neuronal GRP 742. Neuroendocrine GRP 75
C. Molecular Genetics of the Prepro-GRP Gene 75I. The Human Prepro-GRP Gene 75
1. Structure 752. Expression 763. Regulation 77
II. Rat Prepro-GRP Gene 771. Structure 772. Expression 78
III. Human Pro-GRP-Derived Peptides 781. Posttranslational Processing 782. Expression 79
D. Pharmacological Effects of Bombesin and GRP 80I. Effects Unrelated to Growth 80
1. In Vivo Effects 802. In Vitro Effects on Isolated Organs 833. Direct Effects and Cellular Distribution of Receptors . . 854. Induced Release of Endogenous GRP 85
II. Effect on Growth 861. In Vitro Studies 862. In Vivo Studies 88
E. Cellular Responses to Bombesin and GRP 89I. Introduction to Bombesin-Mediated Signal Transduction . . 89
II. Bombesin Binding to Cells/Membranes: Definition of theBombesin Receptor 89
III. Desensitization/Internalization of the Receptor 91IV. Phospholipase Activation 91V. Guanine Nucleotide-Binding Protein/Bombesin Receptor
Interaction ); . . . 93VI. Ion Fluxes . . 95
VII. Protein Phosphorylation . 96VIII. Bombesin Receptor Antagonists 97
IX. Consequences of Bombesin-Evoked Second MessengerProduction 981. Secretion . 982. Receptor Transmodulation 993. Protooncogene Expression 994. DNA Synthesis . 100
F. Conclusions 101Appendix 101References 104
XIV Contents
CHAPTER 22
Platelet-Derived Endothelial Cell Growth FactorK. MIYAZONO and C.-H. HELDIN. With 4 Figures 125
A. Introduction 125B. Purification and Biochemical Characterization of PD-ECGF . . .126
I. Purification of PD-ECGF 126II. Structural Properties of PD-ECGF 128
C. Primary Sequence of PD-ECGF 129D. Biological Activities of PD-ECGF 130
I. In Vitro Effects of PD-ECGF 130II. In Vivo Effects of PD-ECGF 131
E. Conclusion 132References 132
CHAPTER 23
Nerve Growth FactorM. V. CHAO. With 7 Figures . 135
A. Introduction 135B. Nerve Growth Factor Gene Structure 135
I. Nerve Growth Factor Protein Complex 135II. Gene Structure 136
III. Nerve Growth Factor Gene Promoter 137IV. Amino Acid Sequence 138V. Expression of Cloned NGF 140
VI. The a- and y-Subunits 140C. In Vivo Expression of NGF 142D. Mechanism of Signal Transduction 143
I. Second Messengers 143II. Role of Oncogenes :. . . . 145
III. Genes Induced by NGF \. A . 1461. Early Response Genes 1462. Later Responses 148
E. Receptor for NGF 148I. Biochemical Analysis 149
II. Cloning of the NGF Receptor Gene 150III. Features of the NGF Receptor Gene .152IV. Kinetic Forms of the NGF Receptor 154V. Expression of Cloned NGF Receptors 155
F. Conclusions 156References 157
Contents XV
CHAPTER 24
A Glia-Derived Nexin Acting as a Neurite-Promoting FactorD. MONARD 167
A. Introduction 167B. A Glia-Derived Neurite-Promoting Factor Acting as a Protease
Inhibitor 167I. Biochemical Properties 167
II. Molecular Cloning 168III. Characteristics of the Primary Structures 168IV. Biological Effects 170V. Localization of Glia-Derived Nexin 171
VI. Glia-Derived Nexin, a Representative of a New Family ofNeurite-Promoting Factors? 172
VII. Mode of Action of GDN? 173VIII. In Vivo Relevance of the Balance Between Proteases and
Protease Inhibitors for Neurite Outgrowth? 174C. Conclusion 174References 175
CHAPTER 25Mullerian Inhibiting SubstanceR. L. CATE, P. K. DONAHOE, and D. T. MACLAUGHLIN. With 7 Figures . 179
A. Introduction 179B. Structure of MIS 180
I. Bovine and Chicken MIS Proteins 180II. Bovine and Human MIS Genes 182
III. Biosynthesis of Human MIS in CHO Cells 185C. MIS as a Member of the TGF-J? Family 186
I. Structural Properties of the Family \ . . . 186II. Proteolytic Processing of Human MIS } . . . 188
D. MIS Expression During Development . 190I. Upstream Regions of the Bovine and Human MIS Genes . .190
II. Expression of MIS in the Testis 194III. Expression of MIS in the Ovary 196
E. Mechanism of Action . 198I. MIS Receptor and Mullerian Duct Regression 198
II. Modulators of MIS Action and Mullerian Duct Regression . 200F. Potential Activities of MIS 201
I. Descent of the Testis 201II. Fetal Lung Development 202
III. Antiproliferative Effects of MIS 202G. Summary 203References 204
XVI Contents
CHAPTER 26
The Inhibin/Activin Family of Hormones and Growth FactorsW. VALE, A. HSUEH, C. RIVIER, and J. Yu. With 4 Figures 211
A. Chemical Characterization of Inhibins and Activins 211I. Inhibin 211
II. Activin 216B. Actions of Inhibin and Activin on the Anterior Pituitary 217C. Development of Antisera Toward Inhibin Subunits 219D. Gonadal Production of Inhibin 220
I. Granulosa Cells 220II. Sertoli Cells 221
E. Intragonadal Actions of Inhibin and Activin 221I. Paracrine Regulation 222
II. Autocrine Regulation 222F. Role of Inhibin in Regulation of FSH Secretion In Vivo 223
I. Female Rat 223II. Male Rat 226
G. Tissue Expression of Inhibin Subunits 227H. Inhibin and Activin in the Placenta 228I. Activin and the Control of Oxytocin Secretion 229J. Roles of Activin and Inhibin in Erythropoiesis 229
I. Complexity of Hematopoietic Control 230II. Induction of Erythroid Differentiation 231
III. Potentiation of Erythroid Colony Formation 232IV. Expression of Activin/Inhibin Subunits in Hematopoietic Cells 234
K. Conclusions 235References 236
CHAPTER 27Mammary-Derived Growth InhibitorR. GROSSE and P. LANGEN. With 4 Figures . 249
A. Introduction 249B. Results 250
I. Purification 250II. Amino Acid Sequence Determination and Sequence Homologies 252
HI. Cellular Activities 2551. Ehrlich Ascites Carcinoma Cells 2552. Mammary Epithelial Cell Lines 259
IV. Biochemical and Cellular Mechanism of Action 2601. Interaction with Hydrophobic Ligands 2602. Possible Role of Ribonucleotide Reductase 261
C. Conclusions 262References 263
Contents XVII
CHAPTER 28
Pentapeptide Growth InhibitorsW. R. PAUKOVITS, K. ELGJO, and O. D. LAERUM. With 13 Figures . . . 267
A. Hemoregulatory Peptide 268I. Preparation of the Hemoregulatory Peptide 268
1. Sources 2682. Fractionation 269
II. Structural Studies 270III. Synthesis 271IV. Biological Activities on Normal Hematopoiesis 272
1. Growth-Promoting Activity of HP5b Dimer 2722. Growth Inhibitory Activity of HP5b Monomer 2743. Effects on Leukemic Cell Lines 2764. Specificity Tests and Activities not Related to Growth . . 276
V. Effects on Perturbed Hematopoiesis 2781. Inhibitory Effects of HP5b Monomer 2782. Possible Clinical Implications 279
VI. Biochemical and Cellular Mechanisms of Action 280B. Epidermal Inhibitory Pentapeptide 281
I. Purification Procedures 281II. Biological Properties 282
III. Long-Term Effects 285IV. Repeated Treatments with the Epidermal Pentapeptide . . . 286V. Tissue Specificity 287
VI. Epidermal Regeneration and Malignancy 288VII. Species Specificity 288
VIII. Toxicity , 289IX. Precursors 289X. Possible Clinical Applications 289
C. Conclusion 290References ; 291
Section C: Coordinate Actions of Growth Factorsin Specific Tissues or Cells
CHAPTER 29
Coordinate Actions of Hematopoietic Growth Factors in Stimulationof Bone Marrow FunctionM.A. S.MOORE. With 11 Figures 299
A. Introduction 299B. Stem Cells, Growth Factors, and the Extracellular Matrix . . . . 299C. Hematopoietic Growth Factor Interactions with Early Stem Cells . 301
XVIII Contents
I. Hematopoietic Growth Factor Interactions in the HPP-CFUAssay 301
II. Action of IL-1 in Short-Term Marrow Suspension Culture(Delta Assay) 303
III. Hematopoietic Growth Factor Interactions in the Blast CellColony Assay 306
IV. Inhibitory Influences on Hematopoietic Stem Cells andProgenitor Cells 308
D. Synergistic Interactions Between IL-1, IL-3, and IL-5 in theProduction and Activation of Eosinophils 309
E. Hematopoietic Growth Factors and Basophil/Mast Cell Development 312F. Preclinical In Vivo Experience with Hematopoietic Growth Factors 314
I. Murine Studies 3141. In Vivo Interaction Between IL-1 and G-CSF in Mice
Treated with 5-FU 317II. Primate Studies 320
G. Clinical Experience with G- and GM-CSF 321I. CSFs in Chemotherapy-Induced Neutropenia 321
II. CSFs in Autologous Bone Marrow Transplantation 325III. CSFs in Myelodysplastic Syndromes 326IV. In Vivo Studies of G-CSF in Congenital and Idiopathic
Neutropenia 329H. Conclusions 333References 335
CHAPTER 30Peptide Growth Factors and the Nervous SystemM. E. GURNEY 345
A. Embryogenesis of Neural Tissues \ . . 345B. Progenitor Cells in the Neural Crest . 345
I. Melanocytes Are a Terminally Differentiated Cell Type . . '. 346II. Heterogeneity of Cell Types Within the Neural Crest . . . . 347
III. SIF Cells Arise from HNK-1 + Progenitor Cells 348IV. SIF Cells Are Bipotential Progenitor Cells Within the
Sympathoadrenal Lineage : 348V. Does NGF Direct SIF Cells Toward Production of
Sympathetic Neurons In Vivo? 349VI. Neurotransmitter Choice is Determined by Environmental
Factors 350C. CNS Progenitor Cells Give Rise to Both Neurons and Glial Cells . 351D. Identification of CNS Progenitor Cells In Vitro 353E. The O2A Glial Lineage 355
I. PDGF is Mitogenic for O2A Progenitor Cells 357
Contents XIX
II. IGF-1 and CNTF Direct the O2A Lineage Toward Productionof Oligodendrocytes or Type-2 Astrocytes 358
F. Neural Growth Factors 360References 363
CHAPTER 31
Role of Growth Factors in Cartilage and Bone MetabolismJ. PFEILSCHIFTER, L. BONEWALD, and G. R. MUNDY 371
A. Origin of Growth Factors in Bone and Cartilage 372B. Receptors for Growth Factors in Bone and Cartilage 374C. Growth Factors in Bone Formation 375D. Growth Factors in Cartilage 380E. Growth Factors in Bone and Cartilage Induction 383F. Regulation of Growth Factor Activity in Bone and Cartilage . . . 383G. Growth Factors and Cartilage Destruction 386H. Growth Factors and Disorders of Bone and Cartilage 387I. Potential for Growth Factors as Therapeutic Agents in Diseases
of Bone Loss 388References 388
CHAPTER 32
Role of Lymphokines in the Immune SystemE. S. VITETTA and W. E. PAUL 401
A. Introduction 401I. Growth Regulation in the Immune System 401
II. Organization of the Immune System 402III. T Lymphocytes 402
1. TH1 and TH2 Cells \ . . . . 402IV. B Cells. . . 403V. Receptor-Mediated Signaling 403
VI. Cognate T-Cell-B-Cell Interactions 404VII. Secreted T-Cell Regulatory Proteins (Lymphokines) . . . . 404
1. Functions of Selected Lymphokines 405VIII. Lymphokines Produced by TH1 and TH2 Cells; Implications
for Immune Functions 407B. Role of Lymphokines in the Immune Response 407
I. T-Cell Subsets . 407II. Functional Differences Between TH1 and TH2 Cells 409
III. Surface Markers of the Different TH-Cell Subtypes 409IV. Proliferative Response of Clones of TH1 and TH2 Cells . . . 410V. Regulation of the Activation of TH1 and TH2 Cells 410
VI. TH1 and TH2 Cells In Vivo 411
XX Contents
C. Action of Lymphokines on Macrophages 412D. Actions of Lymphokines in B-Cell Responses 413
I. Activation 413II. Growth Stimulation 414
III. Differentiation of B Cells into Antibody-Producing Cells . . 414IV. Lymphokine Regulation of Ig Class Switching 415V. B-Cell Growth and Development Control by Action of T-Cell-
Derived Lymphokines 416E. Conclusions 416
I. Lymphoid Organs 417II. Immune Responses Against Bacterial Antigens . . . . . .418
III. Immune Response to Viral Antigens 419IV. Immune Response to Parasites 420V. Concluding Remarks . 420
References 421
CHAPTER 33
Coordinate Actions of Growth Factors in Monocytes/MacrophagesC . F . N A T H A N 427
A. Introduction 427B. Migration 430C. Extramedullary Proliferation 431D. Changes in Shape 433E. Endocytosis, Cell Surface Receptors, and Antigens 434
I. Endocytic Receptors 434II. Other Surface Antigens 435
F. Secretion 436I. Cytokines 437
II. Complement Components and Other Proteases 'i . . 437III. Sterols . 437IV. Reactive Intermediates of Oxygen and of Nitrogen . . . . . 438
G. Activation 438I. Killing of Microbial Pathogens 438
II. Killing of Host-Type Cells 444III. Promotion of Wound Healing 446IV. Generation of Inflammatory and Immune Responses . . . . 446V. Scavenging of Senescent Cells 447
H. Deactivation 447I. Mechanisms of Action of Cytokines on Macrophages 450J. Autocrine Effects 451
K. Polymorphonuclear Leukocytes 451L. Conclusions 452References . . . 453
Contents XXI
CHAPTER 34
Extracellular Matrices, Cells, and Growth FactorsG. R. MARTIN and A. C. SANK. With 3 Figures 463
A. Introduction 463B. Nature of Extracellular Matrices 464
I. Collagens 464II. Glycoproteins 464
III. Proteoglycans 465IV. Matrix Molecules in Supramolecular Complexes 466
C. Cell-Matrix Interactions 466I. Fibronectin 466
II. Laminin 467III. Collagen 468IV. Matrix Receptors 468
D. Role of Matrix Molecules in Cell Growth 469I. Storage Sites for Growth Factors 469
II. Mitogenic Activities of Fibronectin and Laminin 469III. Termination of Proliferation by Collagen 470
E. Induction of Collagenase by Growth Factors - Role in Proliferation 472References 474
Section D: Processes Regulated by Growth Factors
CHAPTER 35
Induction of Proteases and Protease Inhibitors by Growth FactorsD. E. MULLINS and D. B. RIFKIN 481
A. Introduction 481B. Fibroblast Growth Factor 481C. Transforming Growth Factor-jS 484D. Platelet-Derived Growth Factor 488E. Epidermal Growth Factor 489F. Interleukin-1 494
I. Hemostasis 494II. Cancer 495
III. Glomerulonephritis 496IV. Arthritis 496
G. Tumor Necrosis Factor . 499H. Colony-Stimulating Factor 1 500I. Discussion 501
References 502
XXII Contents
CHAPTER 36
Inflammation and RepairH. L. WONG and S. M. WAHL. With 1 Figure 509
A. Introduction 509B. Inflammatory Phase: Inflammatory Cell Recruitment and Function 511
I. Platelets 511II. Neutrophils 513
III. Monocytes/Macrophages 514IV. Lymphocyte Function and Regulation 521
C. Proliferative Phase 524I. Regulation of Fibroblast Proliferation 524
II. Extracellular Matrix Synthesis 5271. Collagen 5272. Proteoglycans 5293. Fibronectin 529
III. Endothelial Cell Function and Angiogenesis 530D. Remodeling Phase: Matrix Turnover and Fibrotic Disorders . . . 532E. Concluding Remarks 534References 537
CHAPTER 37AngiogenesisM. KLAGSBRUN and J. FOLKMAN. With 1 Figure 549
A. Introduction 549B. Bioassays for Angiogenesis 550
I. In Vivo Methods 550II. In Vitro Methods 552
C. Angiogenic Factors 553I. Fibroblast Growth Factors ; . . 553
II. Angiogenin . 556III. Transforming Growth Factor-a 557IV. Transforming Growth Factor-)? 558V. Tumor Necrosis Factor 559
VI. Platelet-Derived Endothelial Cell Growth Factor 560VII. Angiotropin 560
VIII. Low Molecular Weight Nonpeptide Angiogenesis Factors . . 561IX. Mechanisms of Angiogenesis Factor Action 562
D. Physiological Regulation of Angiogenic Molecules 563I. Role of Extracellular Matrix in Modulating Angiogenic
Factors 564II. Mast Cells and Heparin as Potentiators of Angiogenesis . . 565
III. Storage of Basic FGF in Basement Membrane - Role ofHeparan Sulfate 565
Contents XXIII
IV. Regulation of Angiogenic Factors by Pericytes 566V. Endocrine Regulation of Angiogenesis 567
1. Ovary 5672. Endometrium 5673. Placenta 568
VI. Role of Hypoxia in Regulating Angiogenic Factors . . . . 568E. Pathological Angiogenesis 569F. Angiogenesis Inhibitors 570G. Future Directions 573References 574
CHAPTER 38
MetastasisE. SCHIFFMANN, M. L. STRACKE, and L. A. LIOTTA. With 10 Figures . . 587
A. Introduction 587B. Invasion as an Active Process 587C. Interaction of Tumor Cells with the Extracellular Matrix 588D. Three Stages in Invasion 589E. Agents Inducing Migration: Autocrine Motility Factors 590F. Melanoma Autocrine Motility Factor 591
I. Isolation and Characterization 593II. Some Chemical Properties of the Protein 593
III. Signal Transduction in Tumor Cells 593G. Unique Features of Tumor Cell Motility 598H. Growth Factors as Motility Stimulants .599
I. Thrombospondin 599II. Bombesin 599
III. Insulin-Like Growth Factors 600I. Autocrine Motility Responses in Nontransforrried Cells 603J. Autocrine Motility Factors as Markers of Malignancy . . \. . . . 605
References 606
CHAPTER 39Expression of Growth Factors and Their Receptors in DevelopmentD. C. LEE and V. K. M. HAN . , . . 611
A. Introduction 611B. The EGF/TGF-a Family of Growth Factors 613
I. Epidermal Growth Factor 6131. Introduction 6132. Developmental Expression of the EGF Receptor 6133. Biological Actions of Exogenous EGF 6144. Developmental Expression of EGF 6165. Transplacental Transport of Maternal EGF 617
XXIV Contents
II. Transforming Growth Factor-ot 6181. Introduction 6182. Developmental Expression of TGF-a 618
III. Link Between EGF-Related Growth Factors and HomeoticLoci 621
IV. Developmental Expression of the Neu Oncogene 622C. j8-Type TGFs 623
I. Introduction 623II. Developmental Expression of TGF-/? 624
III. Role for TGF-/? in Amphibian Development 627D. Insulin-Like Growth Factors/Somatomedins 627
I. Introduction 627II. Expression of IGF Receptors and Binding Proteins 628
III. IGFs in Fetal Tissues and Fluids 629IV. Developmental Expression of IGF Genes 630
E. Platelet-Derived Growth Factor 633I. Introduction 633
II. Developmental Expression of PDGF 633F. Fibroblast Growth Factor and Related Molecules 634
I. Introduction 634II. Developmental Expression of FGF 635
III. Developmental Expression of Related Molecules 636G. Hematopoietic Growth Factors 637
I. Colony-Stimulating Factor 1 and Its Receptor {c-fms) . . . . 6371. Introduction 6372. Developmental Expression of c-fms 638
II. Related Growth Factors 639III. Interleukins-2 and -4 639
H. Nerve Growth Factor 640I. Introduction 640
II. Localization of NGF and Its Receptor \. . . 641I. Conclusions \ • • 643
References . 643
CHAPTER 40
Relationships Between Oncogenes and Growth ControlA. LEUTZ and T. GRAF. With 2 Figures 655
A. Introduction 655B. Growth Factor Genes 657
I. Growth Factor-Type Oncogenes 6581. The v-sis Oncogene 6582. The int-l and int-2 Oncogenes 6593. The hst Oncogene 660
Contents XXV
II. Growth Factor Genes Experimentally Shown to be Capableof Acting as Oncogenes 660
C. Signal Transducer Genes 662I. Receptor Tyrosine Kinase-Type Oncogenes 662
1. The v-erbB Oncogene 6622. The v-fms Oncogene 6643. Other Receptor-Type Tyrosine Kinase Oncogenes . . . . 665
II. Tyrosine Kinase-Type Oncogenes Lacking a TransmembraneDomain 667
III. The ras Family Oncogenes 668IV. Serine Threonine Kinase-Type Oncogenes 669
D. Genes Encoding Nuclear Proteins 671I. Immediate Early Genes 672
1. The fos Gene Family 6722. They'wn Gene Family 673
II. Early Genes 6751. The myc Gene Family 675
III. Hormone Receptor Genes 6761. The erbA Gene Family 676
IV. Other Nuclear Oncogenes 6761. The myb Gene Family 6762. The ets Gene Family 6773. The p53 Oncogene 678
E. Cooperation Between Oncogenes 678References 683
Appendix A. Alternate Names for Growth Factors 705
Appendix B. Chromosomal Locations of Growth Factors/Growth FactorReceptors \ . . . 709
Subject Index 711