Peptide Growth Factors and Their Receptors I

ISBN-13: 9783642492976 / Angielski / Miękka / 2012 / 794 str.

Michael B. Sporn; Anita B. Roberts

Opis

This two-volume treatise, the collected effort of more than 50 authors, represents the first comprehensive survey of the chemistry and biology of the set of molecules known as peptide growth factors. Although there have been many symposia on this topic, and numerous publications of reviews dealing with selected subsets of growth factors, the entire field has never been covered in a single treatise. It is essential to do this at the present time, as the number of journal articles on peptide growth factors now makes it almost impossible for anyone person to stay informed on this subject by reading the primary literature. At the same time it is becoming increasingly apparent that these substances are of universal importance in biology and medicine and that the original classification of these molecules, based on the laboratory setting of their discovery, as "growth factors," "lymphokines," "cytokines," or "colony- stimulating factors," was quite artifactual; they are in fact the basis of a com- mon language for intercellular communication. As a set they affect essentially every cell in the body, and in this regard they provide the basis to develop a unified science of cell biology, germane to all of biomedical research. This treatise is divided into four main sections. After three introductory chapters, its principal focus is the detailed description of each of the major peptide growth factors in 26 individual chapters.

Spis treści

Section A: Introduction.- 1 The Multifunctional Nature of Peptide Growth Factors.- A. Introduction.- B. Autocrine, Paracrine, and Endocrine Mechanisms of Action.- C. Range of Target Cells for Peptide Growth Factors.- D. Contextuality of Action.- E. Nuclear Transcription Factors are also Multifunctional.- F. Role of Extracellular Matrix in Mediating Interactions Between Cells.- G. Therapeutic Implications.- References.- 2 Isolation and Characterization of Growth Factors.- A. Introduction.- B. Insulin.- C. Nerve Growth Factor.- D. Epidermal Growth Factor.- E. Insulin-Like Growth Factors.- F. Platelet-Derived Growth Factor.- G. Fibroblast Growth Factors.- H. Transforming Growth Factors.- I. TGF-?.- II. TGF-?.- I. Interleukins.- J. Hemopoietic Growth Factors.- K. Concluding Remarks.- References.- 3 Properties and Regulation of Receptors for Growth Factors.- A. Introduction.- B. Extracellular Domain Structures of Growth Factor Receptors.- C. Ligand Binding Regions of Extracellular Domains.- D. Extracellular Receptor Domains as Serum Receptors.- E. Multiple Ligand Binding Capabilities of Growth Factor Receptors.- F. Regulation of Cell Surface Ligand Binding.- G. Transmembrane Domains.- H. Cytoplasmic Tyrosine Kinase Domain Structures.- I. Regulation of Receptor Tyrosine Kinases.- J. Cytoplasmic Domains Lacking Tyrosine Kinase Sequences.- K. Conclusions.- References.- Section B: Individual Growth Factors and Their Receptors.- 4 The Epidermal Growth Factor Family.- A. Introduction.- B. Structural Properties of the Growth Factors.- I. Amino Acid Sequences.- II. Related Sequences.- III. Physical Properties.- IV. High Resolution Structure.- 1. Polypeptide Backbone.- 2. Aromatic Clusters.- 3. TGF-? and EGF Comparisons.- 4. Hybrid Molecules.- V. Structure-Function Relationships.- 1. Site-Directed Mutagenesis.- 2. Growth Factor Fragments.- C. Precursor Molecules.- I. EGF.- II. TGF-?.- III. Pox Virus Growth Factors.- D. Growth Factor Genes.- I. Chromosomal Localization.- II. Gene Organization.- 1. Human EGF.- 2. Human TGF-?.- III. Gene Expression.- 1. EGF.- 2. TGF-?.- 3. Pox Virus Growth Factors.- E. The EGF Receptor.- I. Receptor Structure.- II. Receptor Gene.- 1. Chromosomal Localization.- 2. Gene Organization.- 3. Gene Expression.- III. Receptor Life Cycle.- 1. Biosynthesis.- 2. Endocytosis and Degradation.- IV. Receptor Function.- 1. Heterologous Receptor Expression.- 2. Mutants.- 3. Receptor Activation.- 4. Receptor Substrates.- 5. Activation of Gene Expression.- F. Physiology of the EGF Family.- I. EGF.- 1. Distribution in Fluids/Secretions.- 2. Biological Responses.- II. TGF-?.- III. Amphiregulin.- IV. Pox Virus Growth Factors.- G. Role in Transformation.- I. Growth Factor Studies.- 1. Correlative Information.- 2. Transfection Studies.- II. Receptor Studies.- 1. Correlative Information.- 2. Transfection Studies.- References.- 5 Platelet-Derived Growth Factor.- A. Introduction.- B. PDGF Molecules.- I. Multiple Forms and Amino Acid Sequence.- 1. Two Distinct but Homologous Chains Comprise PDGF.- 2. Structural Heterogeneity of PDGF.- 3. Structural Features of the PDGF Molecules.- 4. Structural Conservation of the PDGF Molecule.- II. Gene Structure of the A and B Chains of PDGF.- 1. Characteristics of the A-Chain Gene.- 2. Characteristics of the B-Chain Gene.- 3. Comparison of the A- and B-Chain Genes.- III. Expression and Secretion of PDGF by Normal Cells.- 1. PDGF is Expressed at Low or Undetectable Levels in Normal Cells.- 2. Inducible Expression and Secretion of PDGF.- IV. Expression and Secretion of PDGF in Transformed Cells.- V. Processing and Cellular Localization of PDGF Isoforms.- 1. Simian Sarcoma Virus-Transformed Cells.- 2. c-sis-Transformed Cells.- 3. PDGF A-Chain Transfectants.- 4. Cells Expressing Recombinant PDGF-AB Heterodimers.- 5. Transformed Cells.- 6. Normal Cells.- C. PDGF Receptors.- I. General Models of Receptor Structure and Properties.- 1. Old and New Models of the Structure of the PDGF Receptor.- II. Binding Properties of the PDGF Receptor.- 1. Practical or Technical Concerns.- 2. Receptor Specificity.- 3. Receptor Affinity and Number.- III. Cloning and Expression of Receptor cDNAs.- 1. The Receptor ?-Subunit cDNA.- 2. The Receptor ?-Subunit cDNA.- IV. The Receptor Subunit Genes.- V. Physical Characteristics of PDGF Receptor Proteins.- 1. Size of the PDGF Receptor Based on Affinity Crosslinking Studies.- 2. Size of the Mature Receptor Subunits Based on Metabolic Labeling Data.- 3. Isoelectric Point of Receptor Subunits.- VI. Biosynthesis and Turnover of Receptor Subunits.- 1. Predictions about ?-Subunit Biosynthesis Based on cDNA Sequence.- 2. Experimentally Determined Rates of Biosynthesis and Turnover of the ?-Subunit.- 3. Biosynthesis of the ?-Subunit.- VII. Purification of Receptor Proteins.- VIII. Activities of PDGF Receptors.- 1. Ligand-Induced Internalization.- 2. Ligand-Induced Receptor Autophosphorylation.- IX. Pattern of Expression of PDGF Receptors.- 1. Numbers of Receptors on Different Cell Types.- 2. Relative Levels of Expression of the Two Receptor Subunits in Different Cell Types.- X. Regulation of Expression or Properties of PDGF Receptors.- 1. Regulation of the Affinity of the PDGF Receptor.- 2. Acute Regulation of PDGF Receptor Expression.- 3. Regulation of PDGF Receptor Expression in Potential PDGF Autocrine Systems.- 4. Regulation of PDGF Receptor Expression During Embryogenesis, Development, and Wound Healing.- 5. Receptor Expression In Vivo.- D. In Vivo Clearance of PDGF and PDGF-Binding Proteins.- I. Rapid In Vivo Clearance of PDGF-AB.- II. PDGF-Binding Proteins.- E. Biochemical and Cellular Mechanism of Action.- I. Coordinate Control of Cell Proliferation by PDGF and Plasma Components.- II. Phospholipase Activation and Prostaglandin Metabolism.- III. Modulation of Ion Flux.- IV. Tyrosine Phosphorylation.- V. PDGF Induction of “Early Genes”.- F. Biological Activity of PDGF in Vitro and In Vivo.- I. Direct and Indirect Effects of PDGF on Cell Growth In Vitro.- 1. Direct Mitogenic Response to PDGF.- 2. Indirect Effects of PDGF on Cell Growth.- II. Other In Vitro Activities of PDGF.- 1. Directed Cell Migration and Cell Activation in Response to PDGF.- 2. Modification of Cellular Matrix Constituents.- 3. Vasoconstriction.- III. PDGF In Vivo and Clinical Applications.- 1. Wound Repair.- 2. Embryogenesis and Development.- 3. Atherosclerosis.- 4. Neoplasia and Transformed Cells.- 5. Inflammatory Joint Disease.- 6. Fibrosis.- 7. Other Possible Disease Associations References.- References.- 6 Insulin-Like Growth Factors.- A. Overview.- B. Genes and Proteins.- I. IGF-I and IGF-II Proteins.- 1. IGF-I in Different Species.- 2. IGF-II Variant Proteins.- 3. Structure-Function Analysis of IGF-I.- II. Biosynthetic Precursors.- 1. IGF-II.- 2. IGF-I.- III. IGF-II Gene Expression.- 1. Multiple IGF-II RNA Transcripts from One Gene.- 2. Tissue and Developmental Expression.- 3. Hormonal Regulation.- 4. Tumors.- IV. IGF-I Gene Expression.- 1. Multiple IGF-I Transcripts from a Single Gene.- 2. Tissue and Developmental Expression.- 3. Regulation of IGF-I mRNA.- 4. Tumors.- C. Receptors.- I. Introduction.- II. IGF-I Receptor.- 1. Structure.- 2. Receptor Heterogeneity.- 3. Biosynthesis.- 4. Tyrosine Kinase Activity.- 5. Mediation of Biological Responses to IGF-I and IGF-II.- 6. Signaling.- III. IGF-II/Man-6-P Receptor.- 1. Identification of the IGF-II Receptor as the Cation-Independent Man-6-P Receptor.- 2. Receptor Size.- 3. Binding Affinity for IGF-I.- 4. Biosynthesis.- 5. Regulation.- 6. Signaling by the Receptor.- 7. The IGF-II/Man-6-P Receptor is Present in the Circulation.- 8. Developmental Expression of Tissue Receptor.- D. Binding Proteins.- I. Introduction.- II. Assays for IGF Binding Proteins.- 1. Binding of 125I-Labeled IGFs.- 2. Affinity Crosslinking and SDS Gel Electrophoresis.- 3. Radioimmunoassay.- 4. SDS Gel Electrophoresis and Electroblotting.- 5. Hybridization.- 6. Nomenclature.- 7. Differentiation from IGF-II/Man-6-P Receptors.- III. Purification of Binding Protein Components and Development of Radioimmunoassays.- 1. GH-Dependent Binding Proteins.- 2. Non-GH-Dependent Binding Proteins.- IV. Cloning and Expression of IGF Binding Proteins.- 1. Human BP-25.- 2. Rat BP-3A.- 3. Human BP-53.- 4. Relationship Among the Three Cloned IGF Binding Proteins.- V. Regulation of Individual IGF Binding Proteins in Serum.- 1. Human.- 2. Rat BP-3A.- 3. Pig BP-53.- VI. Fragments of IGF Binding Proteins that Bind IGFs.- 1. BP-53.- 2. BP-25.- 3. BP-3A.- 4. Identification of a Possible Binding Domain.- VII. Binding Specificity of IGF Binding Proteins.- VIII. Occurrence and Distribution of IGF Binding Proteins.- 1. Biological Fluids.- 2. Tissues.- 3. Cells.- 4. Clinical States.- IX. Role of IGF Binding Proteins.- 1. In Vivo.- 2. In Vitro.- X. Sites on IGF-I Recognized by IGF Binding Proteins.- 1. Two-Chain Insulin-IGF-I Hybrid Molecules.- 2. Truncated Destri-IGF-I.- 3. Site-Directed Mutagenesis.- E. Biological Role and Clinical Implications.- I. Diverse Biological Roles.- II. In Vivo Actions: IGF-I.- III. In Vivo Actions: IGF-II.- IV. Conclusion.- References.- 7 Fibroblast Growth Factors.- A. Introduction.- B. Isolation and Characterization of Acidic and Basic FGFs.- I. Amino Acid Sequences of Acidic and Basic FGFs.- II. Microheterogeneous Forms of Acidic and Basic FGFs.- III. An FGF Family of Related Growth Factors.- IV. Molecular Biology of FGFs.- V. Homologies Between Species.- C. Biosynthesis of FGFs.- I. Biosynthesis of Acidic FGF.- II. Biosynthesis of Basic FGF.- D. Distribution of FGFs in Tissues and Cells.- I. FGF-Like Growth Factors and Their Identity with FGF.- II. FGFs in Serum and Physiological Fluids.- E. Mechanism of Action of FGFs.- I. Target Cells.- II. The FGF Receptor.- III. Signal Transduction.- IV. Cellular Responses to FGFs.- F. Structure-Activity Relationships.- I. Receptor, Heparin, and Copper Binding Domains.- II. Interactions with Heparin.- III. Glycosylation.- IV. Phosphorylation of FGFs.- G. Secretion and Regulation of FGFs.- I. Secretion of Basic and Acidic FGFs.- II. Regulation of FGFs in the Local Environment.- H. Biological Activities of FGF.- I. FGFs as Angiogenic Factors.- 1. Angiogenesis and Reproduction.- 2. Angiogenesis and the Ischemic Response.- 3. Tumor Angiogenesis.- 4. Cell Biology of Angiogenesis.- II. FGFs in Wound Healing and Tissue Repair.- III. Tissue Regeneration.- IV. Embryonic Development and Differentiation.- V. Modulation of Endocrine Function.- VI. FGFs as Neuronotrophic Factors.- VII. FGFs and Diseases of Cell Proliferation.- VIII. Conclusions.- References.- 8 The Transforming Growth Factor-?s.- A. Introduction.- B. Chemistry and Molecular Biology of TGF-?.- I. Bioassays for TGF-?.- II. Multiple Forms of TGF-?.- 1. TGF-?s 1 and 2.- 2. Novel TGF-?s Predicted from cDNA Clones.- 3. Functions of Multiple Forms of TGF-?.- 4. Conservation of TGF-?s in Different Species.- III. The TGF-?1 Gene.- 1. Alternate Splicing of the TGF-?1 Gene.- 2. Characterization of the Promoter for the Human TGF-?1 Gene.- C. The TGF-? Supergene Family.- D. TGF-? Receptors.- E. Antibodies to TGF-?.- I. Antibodies that Block Biological Activity.- II. Antibodies Used in Immunohistochemical Localization of TGF-?.- F. Latent Forms of TGF-?.- G. Biological Activity of the TGF-?s.- I. Multifunctional Nature of TGF-? Action.- II. Activity of TGF-? on Specialized Cells and Tissues.- 1. Mesenchyme: Control of Extracellular Matrix.- 2. Muscle.- 3. Skeleton.- 4. Immune Cells and Hematopoiesis.- 5. Steroidogenic Cells — Ovary, Testis, Adrenal.- 6. Endothelium.- 7. Liver.- 8. Other Epithelia.- III. The Role of TGF-? in Embryogenesis.- H. Biochemical Mechanisms of Action.- I. Receptor Signaling.- II. Transcriptional Activation of Genes by TGF-?.- III. TGF-? as a Potential Mediator of the Action of Retinoids and Steroids.- J. Clinical Relevance of TGF-? in Healing and Disease.- I. The Role of TGF-? in Repair Processes.- II. The Role of TGF-? in Carcinogenesis and Other Proliferative Diseases.- III. Therapeutic Opportunities.- References.- 9 Interleukin-1.- A. Introduction.- I. Cells Producing IL-1.- II. Stimuli Capable of Releasing IL-1.- III. Control of IL-1 Production In Vivo.- B. Molecular Biology of IL-1? and IL-1?.- I. Transcripts and Primary Amino Acid Sequences.- II. Precursor-Product Relationships.- III. Recombinant IL-1 Molecules and Mutants.- IV. IL-1 Peptides.- V. Structural Studies.- C. Gene Structure of IL-1? and IL-1?.- I. Intron-Exon Organization.- II. Genomic Regulatory Elements.- III. Transcriptional Regulation.- D. Cell Biology of IL-1 Secretion.- I. Cellular Physiology.- II. Molecular Biological Studies.- III. Membrane IL-1.- E. IL-1 Receptors.- I. Binding Studies.- II. Cell Biology.- III. Biochemistry and Molecular Biology.- F. Inhibitors and Antagonists of IL-1.- I. Inhibitors.- II. Antagonists.- G. Biochemical Mode of Action.- I. Ion Fluxes.- II. Kinases.- III. Phospholipases.- IV. Transcriptional Effects.- V. Expression of Protooncogenes.- H. Biological Properties.- I. Generalizations.- II. Growth Promoting Activity: IL-1 is a Comitogen.- III. Role of IL-1 in Various Organ Systems.- 1 Immune System.- 2. Hematopoietic System.- 3. Host Defense System.- 4. Cardiovascular—Vascular Endothelial System.- 5. Pulmonary System.- 6. Connective Tissue System, Cartilage, and Bone.- 7. Renal System.- 8. Endocrine System.- 9. Gastrointestinal-Hepatic System.- 10. Dermatologic System.- 11. Nervous System.- I. Potential Therapeutic Utility of IL-1.- J. Conclusions.- References.- 10 Interleukin-2.- A. Introduction.- B. Structure of Human and Mouse IL-2.- C. Structure and Regulation of the IL-2 Gene.- D. The IL-2 Receptor.- E. Regulation of IL-2 Receptor Gene Expression.- F. Involvement of a Common Regulatory Factor and IL-2R? Gene Expression.- G. Intracellular Signal Transduction in the IL-2 System.- H. Dysregulation of the IL-2 System.- I. The IL-2 System and Therapeutic Implications.- J. Concluding Remarks.- References.- 11 Interleukin-3.- A. Introduction.- B. IL-3 Protein Structure.- C. IL-3 Gene Chromosomal Location and Structure.- D. Regulation of IL-3 Production.- E. Origins and Properties of Hematopoietic Growth Factor-Dependent Cells.- F. Structure of the IL-3 Receptor.- G. Biochemical Mechanisms in IL-3 Signal Transduction.- H. Gene Regulation by IL-3.- I. Biological Properties of IL-3 In Vitro and In Vivo.- J. Transformation of IL-3 Lineage Cells.- K. Summary.- References.- 12 Interleukin-4.- A. Introduction.- B. Molecular Cloning of IL-4 cDNA.- I. Multiple Biological Activities Produced by Activated Mouse T-Cell Clones.- II. Isolation of IL-4 cDNA Clones.- III. Structure of IL-4 cDNA Clones and Proteins.- IV. Structure of Chromosomal Genes Encoding Mouse and Human IL-4.- 1. Structure of Mouse and Human IL-4 Genes and Chromosomal Location of Human IL-4 Gene.- 2. Nucleotide Sequence of the Human IL-4 Gene.- 3. Comparison of 5? Flanking Sequences of Mouse and Human IL-4 Genes with Other Lymphokine Genes.- V. Expression of IL-4 mRNA.- C. Biological Activity of IL-4.- I. Discovery and Characterization of the B-Cell Activation Properties of IL-4.- II. T-Cell Growth Factor Activity of IL-4.- 1. Activity on Mature T Cells.- 2. Activity on Thymocytes.- III. Biological Activity on B Cells.- IV. Relationship of IL-4 Effects with IFN-? Effects.- V. Effect of IL-5 on IL-4-Dependent IgE Synthesis.- VI. Effects on Mast Cells.- VII. Effects on Macrophages.- VIII. Effects on Hematopoietic Progenitor Cells.- IX. Other Effects of IL-4.- 1. Induction of Lymphokine-Activated Killer Cell Activity.- 2. Effects on Other Cell Lineages.- D. The IL-4 Receptor.- I. The Murine IL-4 Receptor.- II. The Human IL-4 Receptor.- III. Signaling Events Mediated by IL-4.- E. Concluding Remarks.- I. Dichotomy Between TH1 and TH2 Cells.- II. Effects of IL-4 on B Cells.- III. Effects on Other Cell Types.- IV. Conclusions.- References.- 13 Interleukin-5.- A. Introduction.- B. Historical Background of IL-5.- C. Structure of IL-5 and Its Gene.- I. Cloning of IL-5 cDNA.- 1. SP6 Expression Vector System.- 2. Construction of cDNA Libraries.- 3. Structures of the IL-5 cDNA Clone.- II. Polypeptide Structures of IL-5.- 1. Murine IL-5.- 2. Human IL-5.- III. Structure and Organization of the IL-5 Gene.- 1. Structure of the IL-5 Gene.- 2. Chromosomal Location of the IL-5 Gene.- 3. Expression of IL-5 mRNA in Mouse T Cells.- D. Functional Properties of IL-5.- I. Activities on B Cells.- 1. Roles in B-Cell Response to Antigens.- 2. Induction of IgA Secretion.- 3. Stimulation of B-Cell Growth.- 4. Induction of IL-2 Receptors.- II. Activities on Other Hematopoietic Cells.- 1. Eosinophil Colony Stimulating Factor Activity.- 2. Effects on T Cells.- E. Receptors for IL-5.- I. Binding Assay by Radiolabeled IL-5.- II. Number and Affinity of the IL-5 Receptors.- III. Affinity Crosslinking of Radiolabeled IL-5 with Its Receptor.- F. Summary.- References.- 14 Interleukin-6.- A. Introduction.- B. Historical Overview.- I. B-Cell Stimulatory Factor 2.- II. Hybridoma/Plasmacytoma Growth Factor.- III. IFN-?2 and 26-kDa Protein.- C. Structure of IL-6.- D. Gene Structure and Expression of IL-6.- I. Structure of the IL-6 Gene.- II. Chromosomal Location of the IL-6 Gene and Polymorphism.- III. Regulation of Expression of the IL-6 Gene.- 1. IL-6-Producing Cells.- 2. Stimuli Inducing IL-6 Production.- 3. Mechanisms Regulating IL-6 Gene Expression.- E. Structure and Expression of the IL-6 Receptor.- I. Presence of High- and Low-Affinity Receptors.- II. Structure of the IL-6 Receptor.- F. Biological Activities of IL-6.- I. Lymphoid Tissue.- 1. Effects on B-Lineage Cells.- 2. Effects on T Cells.- II. Hematopoietic Progenitors.- III. Acute Phase Responses.- IV. Neural Cells.- V. Antiviral Activity.- G. Plasma Clearance and Carrier Proteins.- H. IL-6 and Disease.- I. Polyclonal B-Cell Activation and Autoimmune Disease.- II. Lymphoid Malignancies.- 1. Plasmacytoma/Myeloma.- 2. Lennert’s T-Cell Lymphoma.- III. Proliferative Glomerulonephritis.- J. Prospects.- References.- 15 Colony-Stimulating Factor 1 (Macrophage Colony-Stimulating—Factor).- A. Colony-Stimulating Factor 1, a Mononuclear Phagocyte Growth Factor.- B. Assay and Purification of CSF-1.- I. Bioassay and Purification.- II. Radioimmunoassay and Radioreceptor Assay.- C. Molecular Cloning and Predicted Primary Structure of CSF-1.- I. Initial Cloning Strategy.- II. Primary Structure of Human and Murine CSF-1.- D. Mechanisms of CSF-1 Posttranslational Processing and Secretion.- I. Processing of CSF-1224.- II. Processing of CSF-1522.- E. Chromosomal Localization and Organization of the Human CSF-1 Gene.- I. Linkage of CSF-1 and Its Receptor on Human Chromosome 5.- II. Exon—Intron Structure and Alternative Splicing.- F. CSF-1 Gene Expression.- G. The CSF-1 Receptor (c-fms Protooncogene Product).- I. Tissue-Specific Expression.- II. Primary Structure of CSF-1R and the v-fms Oncogene Product.- III. Transforming Potential of Human CSF-1R.- IV. Binding Affinity of CSF-1R for Ligand.- V. Receptor Downregulation and Turnover.- H. Receptor Tyrosine Kinase Activity and Signal Transduction.- J. Physiologic Effects and Agents That Modulate CSF-1 Activity.- I. Direct and Synergistic Effects.- II. CSF-1 Antagonists.- K. Clinical Implications.- References.- 16 Granulocyte Colony-Stimulating Factor.- A. Introduction.- B. Purification of Natural G-CSF.- I. Purification of Mouse G-CSF.- II. Purification of Human G-CSF.- C. Primary Structure of G-CSF.- I. Isolation and Characterization of Human G-CSF cDNA.- II. Isolation and Characterization of Murine G-CSF cDNA.- D. Chromosomal Gene Structure for G-CSF.- I. Location of the G-CSF Gene on Human and Mouse Chromosomes.- II. Structure of the G-CSF Chromosomal Gene.- 1. Structure of the Human G-CSF Chromosomal Gene.- 2. Structure of the Mouse G-CSF Chromosomal Gene.- 3. Promoter of the G-CSF Chromosomal Gene.- E. Expression of the G-CSF Gene.- I. Inducible Expression of the G-CSF Gene.- II. Constitutive Expression of the G-CSF Gene in Carcinoma Cells.- F. Production of Recombinant G-CSF.- G. Function of G-CSF.- I. In Vitro Function of G-CSF.- II. Receptor for G-CSF.- III. In Vivo Function of G-CSF.- IV. Clinical Application of G-CSF.- References.- 17 Granulocyte-Macrophage Colony-Stimulating Factor.- A. Introduction.- B. Discovery and Nomenclature.- C. Biology.- D. Biochemistry.- E. Pharmacological Studies.- F. GM-CSF and Leukemia.- G. Clinical Studies with GM-CSF.- References.- 18 Erythropoietin: The Primary Regulator of Red Cell Formation.- A. Introduction.- B. Chemistry.- C. Molecular Biology.- I. Cloning and Analysis of the Erythropoietin Gene.- II. Chromosomal Localization of the Erythropoietin Gene and Its Restriction Fragment Length Polymorphism.- III. Expression of the Erythropoietin Gene.- IV. Studies of Erythropoietin Gene Expression in Transformed Cells.- D. Specific Erythropoietin Receptors.- E. Mode of Action.- F. Clinical Aspects.- References.- Appendix A. Alternate Names for Growth Factors.- Appendix B. Chromosomal Locations of Growth Factors/Growth Factor Receptors.