CONTENTS List of Participants ... xiii Preface ... xxi OPENING ADDRESS Opening Address : Genes and Proteins in Oncogenesis / HOWARD M. TEMIN Introduction ... 3 Evolution of Highly Oncogenic Retroviruses ... 5 Multistage Carcinogenesis ... 10 Other Carcinogenic Agents ... 10 Conclusions ... 11 Referenes ... 12 PART Ⅰ. DNA MODIFICATION OF CARCINOGENS Conformational Changes in DNA Induced by Chemical Carcinogens / DEZIDER GRUNBERGER ; REGINA M. STNTELLA Introduction ... 13 Conformation of AAF- and AF-Modified DNA ... 14 Z-DNA Conformation in Alternating Purine-Pyimidine Polymers ... 23 Conclusions ... 36 References ... 38 Studies on DNA Damage and Mutagenesis by Ultraviolet Light / KWOK MING LO ; DOUGLAS E. BRASH ; WILLIAM A. FRAN Introduction ... 41 Discussion ... 43 Summary ... 53 References ... 53 Membrane-Mediated Chromosomal Damage / P. A. CERUTTI ; I. EMERIT ; P. AMSTAD Introuction ... 55 The Clastogenic Action in PMA in Human Lymphocytes Is Membrane-Mediated ... 59 Concluding Remards ... 64 References ... 65 Molecular Mechanism of Mutagenesis by the Ultimate Carcinogen N-Acetoxy-N-2-Acetylaminofluorene / ROBERT P. P. FUCHS ; NICOLE KOFFEL-SCHWARTZ ; MIC Introduction ... 69 Materials and Methods ... 70 Results ... 72 Discussion ... 76 Summary ... 80 References ... 81 Nitrated Polycyclic Aromatic Hydrocarbons: A Newly Recognized Group of Ubiquitous Environmental Agents / HERBERT S. ROSENKRANZ ; ELENA C. McCOY ; ROBERT M Text ... 83 References ... 93 PART Ⅱ. MULTISTAGE EVENTS Cellular Events in Multistage Carcinogenesis / I. BERNARD WEINSTEIN ; ANN HOROWITZ ; ALAN JEFFRE Multistage Carcinogenesis ... 99 Mechanism of Action of Tumor Promoters ... 101 Promoter-like Activities of Polycyclic Aromatic Hydrocarbons ... 106 Chromosomal Effects and Activated Oxygen ... 107 Summary ... 108 References ... 109 Potenr New Mutagens from Pyrolystates of Proteins and New Naturally Occurring Potein Tumor Promoters / HIROTA FUGIKI ; TAKASHI SUGIMURA Introduction ... 111 New Mutagens from Pyrolysates of Amino Acids, Proteins, and Proteinaceous Foods ... 112 New Naturally Occurring Potent Tumor Promoters ... 114 Indole Alkaloids : Dihydroteleocidin B, Teleocidin, and Lyngbyatoxin A ... 116 In Vivo Carcinogenicity Test with Dihydroteleocidin B, Teleocidin, and Lyngbyatoxin A ... 118 Polyacetates : Aplysiatoxin and Debromoaplysiatoxin ... 119 References ... 120 Multistage Skin Tumor Promotion in Mouse Skin : Gritical Protein Changes During Tumor Promotion / T. J. SLAGA ; K. G. NELSON Introduction ... 125 Tumor Promotion ... 126 Inhibitors of Tumor Promotion ... 128 Critical Protein Changes During Tumor Promotion ... 130 Multistage Promotion ... 133 Protein Changes in Papillomas and Squamous Cell Carcinomas ... 138 Conclusion ... 140 References ... 141 Tumor Promotion in the Skin of Hairless Mice by Halogenated Aromatic Hydrocarbons / ALAN POLAND ; JOYCE KNUTSON ; EDWARD GLOVER ; AND Introducion ... 143 Epidermal Changes Produced by Halogenated Aromatic Hydrocarbons ... 146 References ... 160 PART Ⅲ. GROWTH FACTORS AND RECEPTORS Transforming Growth Factors Produced by Viral-Transformed and Human Tumor Cells / GEORGE J. TODARO ; HANS MARQUARDT ; DANIEL R. TWA Introduction ... 165 EGF Binding by Retrovirus-Transformed and Human Tumor Cells ... 166 Transforming Growth Factor Production ... 168 Purification of Rat, Mouse, and Human TGFs ... 170 Rat and Human TGF Amino Acid Sequences ... 175 Tyrosine Phosophorylation of the EGF Receptor ... 176 Conclusions ... 180 References ... 181 Receptor-Mediated Endocytosis of Peptide Hormones and Macromolecules in Cultured Cells / MARK C. WILLINGHAM ; IRA H. PASTRN Introduction ... 183 The Morphologic Structures of Endocytosis on the Cell Surface ... 183 Intracellular Fate of the Receptosome ... 191 Compartmentalization within the Golgi System ... 192 Pathologic Processes : Toxins and Viruses ... 193 The Physiological Significance of Coated Pit Endocytosis ... 193 Summary ... 194 References ... 194 Thyroid Dependence of Neoplastic Transformation / DUANE L. GUERNSEY ; CARMIA BOREK ; PAUL B. FISHER Introduction ... 197 Historical Background ... 198 Thyroid Hormone Modulation of Neoplastic Transformation in Cell Culture ... 199 Thyroid Hormone Modulation of Adenovirus Transformation of Cells in Culture ... 204 T3 Nuclear Receptors in Normal and Transformed Cells ... 206 Conclusion ... 208 References ... 208 PART Ⅳ. VIRAL ONCOGENES A Novel Retrovirus, Adult T-Cell Leukemia Virus(ATLV) : Characterization and Relation to Malignancy / YORIO HINUMA Introduction ... 213 Properties of ATLV ... 214 Relation of ATLV to ATL ... 219 Concluding Remarks ... 221 References ... 222 The v-myc and c-myc Genes : Roles In Oncogenesis / WILLIAM S. HAYWARD Introduction ... 225 The c-myc Gene ... 227 Activation of c-myc by ALV ... 228 Conclusions ... 229 References ... 231 Homologous to the mos Transforming Gene of Moloney Sarcoma Virus / ALESIA WOODWORTH ; MARIANNE OSKARSSON ; DONALD G. Introduction ... 223 Results ... 234 References ... 240 Enhanced Expression and Amplification of a Cellular Oncogene in Human Tumors / U. ROVIGATTI ; S. M. ASTRIN Introduction ... 241 Discussion ... 248 References ... 250 Cellular DNA Sequences Involved in Chemical Carcinogenesis / PAUL T. KIRSCHMEIER ; SEBASTIANO GATTONI-CELLI ; Introduction : Genes Involved in Carcinogenesis ... 253 Studies of Celluar one Genes in Normal and Transformed Murine Cells ... 254 Studies on the Expression of Poly (A)+ RNA-Containing LTR-Like Sequences ... 255 Development of an Expression and Transduction Vector ... 260 Transduction with MULV Helper Virus ... 262 Conclusion ... 264 References ... 265 PART Ⅴ. GENE AMPLIFICATION AND TRANSFECTION Gene Amplification and Methotrexate Resistance in Cultured Animal Cells / ROBERT T. SCHIMKE ; PETER C. BROWN ; RANDAL N. JO Introduction ... 269 The Mechanism of Gene Amplification ... 270 Single-Step Selection for Methotrexate Resistance ... 272 Pretreatment Regimens and Enhanced Frequencies of MTX Resistance ... 276 DHER Gene Amplification under Nonselection Conditions ... 277 Discussion ... 279 References ... 282 Identification, Isolation, and Characterization of Three Distinct Human Transforming Genes / M. WIGLER ; M. GOLDFARB ; K. SHIMIZU ; M. PERPUCH Detecting Human Transforming Genes ... 285 Isolating Transforming Genes from Human Sources ... 287 The Relationship of Human Transforming Genes to Known Retroviral Oncogenes ... 288 Activation of Normal Celluar Genes into Transforming Genes ... 290 Conclusion ... 290 References ... 291 PART Ⅵ. TRANSFORMATION-RELATED PROTEINS AND TRANSCRIPTS Do Variant SV40 Squences Have a Role in the Maintenance of the Oncogenic Transformed Phenotype? / ROBERT POLLACK ; CAROL PRIVES ; JAMES MANLEY Introduction ... 295 SV40 Viral Genes and Transformation ... 297 Intial Hypothesis ... 299 References ... 302 Protein Kinases Encoded by Avian Sarcoma Viruses and Some Related Normal Cellular Proteins / R. L. ERIKSON ; TONA M. GILMER ; ELEANOR ERIKSON Introduction ... 305 Results and Discussion ... 306 References ... 320 The Control of Cellular Transcripts in Transformed Cells / ARNOLD J. LEVINE ; TED SCHUTZBANK ; ROBIN ROBINSO Introduction ... 323 Results ... 324 Discussion ... 333 References ... 335 PART Ⅶ. NUCLEAR MATRIX, CYTOSKELETON, AND MITOCHONDRIA IN CARCINOGENESIS The Concept of DNA Rearrangement in Carcinogenesis : The Nuclear Matrix / DONALD S. COFFEY Introduction ... 339 DNA Rearrangement in Cancer ... 339 DNA Rearrangement in Normal Development and Expression of the Oncogene ... 342 Nuclear Structure and Function ... 344 References ... 347 A Point Mutating in β-Actin Gene and Neoplastic Transformation / TAKEO KAKUNAGA ; JOHN LEAVITT ; HIROSHI HAMADA ; Introduction ... 351 A Variant Form of Actin Is Present in a Chemically Transformed Human Cell Line ... 352 A Variant Form of Actin Encoded by the β-Actin Gene That Has a Point Mutation in Its Structural Gene ... 355 Additional Changes in the β-Actin Molecule in a Variant of the Transformed Cells ... 359 Incremental Increases in the Malignancy Associated with Increased Abnormality of Mutated β-Actin Molecules ... 363 A Hypothesis on the Role of Actin Mutation in the Neoplastic Transformation ... 364 References ... 366 Studies of Mitochondria in Carcinoma Cells with Rhodamine-123 / LAN BO CHEN ; THEODORE J. LAMPIDIS ; SAMUEL D. BE Introduction ... 369 Prolonged Retention of Rhodamine-123 by Carcinogen-Transformed Epithelial Cells and Carcinoma-Derived Cells ... 370 Selective Toxicity of Rhodamine-123 in Carcinoma Cells in Vitro ... 375 Rhodamine-123 Selectivity Reduces Clonal Growth in Carcinoma Cells in Vitro ... 377 Anticarcinoma Activity in Vivo of Rhodamine-123 and the Combination Therapy with 2-Deoxyglucose ... 380 Measurement of Rhodamine-123 Uptake by Carcinoma Cells ... 382 Basis for Rhodamine-123 Toxicity ... 384 Summary ... 386 References ... 386 Index ... 389