From a logical point of view, cell division is regulated by the environment and by the ability of the cell to respond to the environmental signals. The terminology of the cell cycle, the elaborate mathematical models, and the kinetic analyses are all convenient notations and descriptions of the behavior of populations of cells. However, they tell us very little about the fundamental molecular mechanisms that control cell proliferation. Stated in other terms, what controls cell reproduction are growth factors in the environment and genes and gene products inside the cell or at its surface. This book examines the aforementioned growth factors, the study of which has made very rapid progress in the past few years. The selection of topics has been influenced by logistic considerations, but the book, as a whole, gives a broad survey of the state of the art of this exciting field. For this, thanks are due to the contributors, who have given much time to the preparation of the manuscripts and have met the deadline with a punctuality that is uncommon among biomedical scientists. I would also like to thank Ms. NORA PERRETT and the staff of Springer-Verlag for their help in editing the manuscripts and in preparing the production of the book.

Inhalt

1 Introduction to Cell Growth: Growth in Size and DNA Replication.- A. Introduction.- B. Doubling of Size in Growing Cells.- C. Replication of DNA in Growing Cells.- D. Independence of Signal to Grow in Size from Signal to Replicate DNA.- E. Mechanism of Action of Growth Factors.- References.- 2 Survival and Growth Requirements of Nontransformed Cells..- A. Definitions.- I. Normal, Nontransformed, and Transformed Cells.- II. Survival and Survival Requirements.- III. Cell Cycle, Growth, Division, Multiplication, and Proliferation.- IV. Nutrient, Growth Requirement, Growth Factor, Mitogen, and Hormone.- B. Assay Systems for the Measurement of Growth Requirements.- I. Background.- II. Inadequacy for Nontransformed Cells of Classic Assay Systems.- 1. Evolutionary Adaptation of Permanent Lines.- 2. Role of Serum in the Multiplication of Nontransformed Cells.- 3. Problems Awaiting Solution for Nontransformed Cells.- III. Holistic Approach to Cellular Growth Requirements.- IV. Development of Specific Assays for Individual Growth Requirements.- 1. Background Media Lacking a Single Growth-Promoting Substance.- 2. First Limiting Factor.- 3. Replaceable Requirements.- 4. Sequential Depletion.- 5. Systematic Testing of Suspected Growth-Promoting Substances.- V. Types of Measurement and Analysis of Data.- 1. Short-Term Vs Long-Term Multiplication.- 2. Sparse Vs Dense Cultures.- 3. DNA Synthesis Vs Increase in Cell Number.- 4. Analysis of Data Based on Total Multiplication.- 5. Analysis Based on Rate of Multiplication.- 6. Multiplication Rate Kinetics.- VI. Systematic Analysis of Growth Requirements.- C. Requirements for Survival and Growth of Nontransformed Cells.- I. Transformed Vs Nontransformed Cells.- II. Requirements Related to Subculturing and Cellular Attachment.- 1. Anchorage Dependence.- 2. Neutralization of the Dispersing Agent.- 3. Low Temperature Trypsinization.- 4. Attachment and Spreading Factors.- 5. The Culture Surface.- 6. Artificial Substitutes for the Basement Membrane.- III. Inorganic Ions, Physical Chemistry, and Cell Physiology.- 1. Bicarbonate, Carbon Dioxide, pH, and Buffering.- 2. Sodium, Chloride, Osmolarity, and Humidification of Incubators.- 3. Potassium and Na+: K+ Ratios.- 4. Calcium, Magnesium, and Regulatory Roles of Divalent Cations.- 5. Phosphate.- 6. Other Physicochemical Parameters.- IV. Qualitative Nutrient Requirements.- 1. Components of Eagle's Minimum Essential Medium.- 2. Other Amino Acids.- 3. Other Vitamins.- 4. Carbohydrates and Intermediates of Energy Metabolism.- 5. Nucleic Acid Components.- 6. Other Organic Nutrients.- 7. Inorganic Trace Elements.- V. Quantitative Optimization of Synthetic Media.- 1. Species and Cell Type Individuality of Quantitative Requirements.- 2. Reduction of Requirements for Serum and Growth Factors.- VI. Lipids and Related Substances.- 1. Fatty Acids.- 2. Prostaglandins.- 3. Phospholipids.- 4. Cholesterol.- 5. Synthetic Media.- VII. Hormones, Hormone-Like Growth Factors, and Carrier Proteins.- 1. Hormones.- 2. Growth Factors.- 3. Replacement of Serum with Hormones and Growth Factors.- 4. Individuality of Cellular Requirements.- 5. Nontransformed Cells.- 6. Relationship to In Vivo Growth Requirements.- VIII. Special Requirements Related to Cellular Density.- 1. Requirements for Clonal Growth.- 2. Requirements for Multiplication of Dense Cultures.- IX. Regulatory Interactions and Artificial Stimulation of Multiplication.- 1. Borderline Toxicity.- 2. Proteolytic Enzymes.- 3. Tumor Promoters.- 4. Inorganic Ions.- 5. Cyclic Nucleotides.- 6. Defining a Genuine Growth Requirement.- D. Requirements for Survival of Nontransformed Cells Without Proliferation.- I. Early Studies.- II. Survival Factor.- III. Elimination of the Need for Survival Factor.- IV. Nutrients and Survival.- V. Differences in Survival Between Nontransformed and Transformed Cells.- E. Future Studies of the Growth and Survival Requirements of Nontransformed Cells.- I. Integration of New Findings.- II. Questions Remaining to be Solved After Development Synthetic Media.- III. Magnitude of Remaining Work.- IV. Selective Allocation of Resources.- F. Summary and Conclusions.- G. Note Added in Proof.- References.- 3 Epidermal Growth Factor.- A. Introduction.- B. Chemical and Physical properties of EGF.- I. Mouse EGF.- 1. Isolation.- 2. Chemical and Physical Properties.- 3. Derivatives.- a) EGF-2.- b) EGF-5.- c) Cyanogen Bromide EGF.- 4. High Molecular Weight Mouse EGF.- II. Human EGF.- 1. Identification and Isolation.- 2. Chemical and Physical Properties.- 3. Relationship of Human EGF and Urogastrone.- III. Rat EGF.- C. Physiological Aspects of EGF.- I. Concentration in Body Fluids.- 1. Mouse EGF.- 2. Human EGF.- II. Localization.- 1. Mouse EGF.- 2. Human EGF.- III. Control of Submaxillary Gland Content of Mouse EGF.- IV. Secretion of Mouse EGF from the Submaxillary Gland.- V. Factors Affecting Levels of Human EGF.- D. Biological Activities of EGF In Vivo.- I. Skin.- II. Corneal Epithelium.- III. Respiratory Epithelium.- IV. Gastrointestinal Tract.- V. Liver.- E. Organ Culture Studies of EGF.- I. Skin.- II. Other Tissues.- 1. Cornea.- 2. Palate.- 3. Bone.- F. Cell Culture Studies of EGF.- I. Cell Nutrition.- II. Types of Cells Affected by EGF.- III. EGF and the Growth of Cell Populations.- IV. Components of the Mitogenic Response.- 1. Rapid Biological Responses at the Membrane.- a) Uridine Uptake.- b) Sugar Transport.- c) Cation Fluxes.- d) Putrescine Transport.- e) Alanine Transport.- f) Membrane Ruffling and Macropinocytosis.- g) Other Membrane Responses.- 2. Responses of EGF Occurring in the Cytoplasm.- a) Activation of Glycolysis.- b) Synthesis of Extracellular Macromolecules.- c) Activation of RNA and Protein Synthesis.- d) Activation of Ornithine Decarboxylase.- e) Protein Phosphorylation.- 3. Stimulation of DNA Synthesis.- V. Responses Not Related to Mitogenesis.- G. Growth Factor: Receptor Interactions.- I. Receptors for EGF.- II. Internalization and Degradation of EGF.- 1. Biochemical Evidence.- 2. Morphological Evidence.- III. Internalization of the Receptor.- 1. Indirect Evidence.- 2. Chemical Evidence.- 3. Morphological Evidence.- IV. Recovery of Receptor Activity.- H. Relationship of EGF Binding and Metabolism to Biological Activity.- I. Rapid Changes in Cell Physiology.- II. Stimulation of DNA Synthesis.- I. Other Controls of Receptor Activity.- I. Transforming Agents.- II. Tumor Promoters.- III. Differentiation.- IV. Lectins and Glycoprotein Metabolism.- V. Glucocorticoids.- VI. Modulation of Protein Synthesis.- K. A Biochemical Response to EGF in Subcellular Systems.- L. Prospectus.- References.- 4 The Platelet-Derived Growth Factor.- A. Serum, the Platelet-Derived Growth…