COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME LIX COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME LIX

The Molecular Genetics of

COLD SPRING HARBOR LABORATORY PRESS 1994 COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY VOLUME LIX 1994 by The Cold Spring Harbor Laboratory Press International Standard Book Number 0-87969-067-4 (cloth) International Standard Book Number 0-87969-068-2 (paper) International Standard Serial Number 0091-7451 Library of Congress Catalog Card Number 34-8174

Printed in the United States of America All rights reserved

COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

Founded in 1933 by REGINALD G. HARRIS Director of the Biological Laboratory 1924 to 1936

Previous Symposia Volumes

I (1933) Surface Phenomena XXVIlI (1963) Synthesis and Structure of Macromolecules II (1934) Aspects of Growth XXIX (1964) Human Genetics III (1935) Photochemical Reactions XXX (1965) Sensory Receptors IV (1936) Excitation Phenomena XXXI (1966) The Genetic Code V (1937) Internal Secretions XXXII (1967) Antibodies VI (1938) Protein Chemistry XXXIII (1968) Replication of DNA in Microorganisms VII (1939) Biological Oxidations XXXIV (1969) The Mechanism of Protein Synthesis VII1 (1940) Permeability and the Nature of Cell Membranes XXXV (1970) Transcription of Genetic Material IX (1941) Genes and Chromosomes: Structure and Organiza- XXXVI (1971) Structure and Function of Proteins at the tion Three-dimensional Level X (1942) The Relation of Hormones to Development XXXVII (1972) The Mechanism of Muscle Contraction XI (1946) Heredity and Variation in Microorganisms XXXVIII (1973) Chromosome Structure and Function XII (1947) Nucleic Acids and Nucleoproteins XXXIX (1974) Tumor Viruses XIII (1948) Biological Applications of Tracer Elements XL (1975) The Synapse XIV (1949) Amino Acids and Proteins XLI (1976) Origins of Lymphocyte Diversity XV (1950) Origin and Evolution of Man XLII (1977) Chromatin XVI (1951) Genes and Mutations XLIII (1978) DNA: Replication and Recombination XVII (1952) The Neuron XLIV (1979) Viral Oncogenes XVIII (1953) Viruses XLV (1980) Movable Genetic Elements XIX (1954) The Mammalian Fetus: Physiological Aspects of XLVI (1981) Organization of the Cytoplasm Development XLVII (1982) Structures of DNA XX (1955) Population Genetics: The Nature and Causes of XLVIII (1983) Molecular Neurobiology Genetic Variability in Population XLIX (1984) Recombination at the DNA Level XXI (1956) Genetic Mechanisms: Structure and Function L (1985) of Development XXll (1957) Population Studies: Animal Ecology and De- LI (1986) Molecular Biology of Homo sapiens mography LII (1987) Evolution of Catalytic Function XXIII (1958) Exchange of Genetic Material: Mechanism and LIII (1988) Molecular Biology of Signal Transduction Consequences LIV (1989) Immunological Recognition XXIV (1959) Genetics and Twentieth Century Darwinism LV (1990) The Brain XXV (1960) Biological Clocks LVI (1991) The Celt Cycle XXVI (1961) Cellular Regulatory Mechanisms LVII (1992) The Cell Surface XXVII (1962) Basic Mechanisms in Animal Virus Biology LVIII (1993) DNA and Chromosomes

Front Cover (Paperback): Retinoblastoma protein forms "corrals" in the nucleus. (For details, see W.-H. Lee et al., p. 103, this volume.) Back Cover (Paperback): H & E staining and immunohistochemical staining with antibodies against von Willebrand factor of lungs of mice after removal of the primary tumor. (For details, see O'Reilly et al., p. 479, this volume.) Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cold Spring Harbor Laboratory for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that the base fee of $5.00 per article is paid directly to CCC, 222 Rosewood Dr., Danvers, MA 01923. [0-87969-067-4/94 $5.00 + .00]. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. All Cold Spring Harbor Laboratory Press publications may be ordered directly from Cold Spring Harbor Laboratory Press, 10 Skyline Drive, Plainview, NY 11803. Phone: 1-800-843-4388 in Continental U.S. and Canada. All other locations (516)349-1930. FAX: (516)349-1946. Symposium Participants

ABEL, KENNETH,Dept. of Internal Medicine, Uni- England Medical Center, Boston, Massachu- versity of Michigan, Ann Arbor setts ADYA, NEERAJ, Dept. of Infectious Diseases, Case BARKARDOTTIR, ROSA, Dept. of and Western Reserve University School of Medi- Cell Biology, University Hospital of Iceland, cine, Cleveland, Ohio Reykjavik AGARWAL, MUNNA, Dept. of Molecular Biology, BARNES, DEBORAH, Journal of NIH Research, Cleveland Clinic Foundation, Cleveland, Washington, D.C. Ohio BARRETT, J. CARL, Lab. of Molecular Carcino- ALBERTS, BRUCE, Dept. of Biochemistry and Bio- genesis, NIH-National Institute of Environ- physics, University of California, San Fran- mental Health Sciences, Research Triangle cisco Park, North Carolina AMARIGLIO, NINET37E, Institute of Hematology, BARTEK, JIRI, Danish Cancer Society, Copen- Chaim Sheba Medical Center, Tel Hash- hagen, Denmark omer, Israel BASlLE, THOMAS, Chadbourne and Parke, New AMFO, KWASI HENRY, Dept. of Medical Genetics, York, New York Free University of Brussels, Belgium BEACH, DAVID, Cold Spring Harbor Laboratory, ANDERS, ROBERT, Dept. of Biochemistry, Mayo Cold Spring Harbor, New York Clinic, Rochester, Minnesota BENFIELD, PAM, Dept. of Molecular Biology, Du ANDO, KIYOSHI,Tokai University School of Med- Pont Merck Pharmaceutical Co., Wilming- icine, Kanagawa, Japan ton, Delaware BENZOW, KELLIE,Virginia Piper Cancer Institute, ANDRULIS, IRENE, Dept. of Molecular and Medi- Abbott Northwestern Hospital, Minne- cal Genetics, Samuel Lunenfeld Research apolis, Minnesota Institute, Mount Sinai Hospital, Toronto, BEPLER, GEROLD, Dept. of Medicine and Molecu- Ontario, Canada lar Cancer Biology, Duke University Medical APLAN, PETER, Dept. of Pediatrics and Molecular Center, Durham, North Carolina Medicine, Roswell Park Cancer Institute, BERNDT, NORBERT, Dept. of Pediatrics, Childrens Buffalo, New York Hospital of Los Angeles, California ARASON, ADALGEIR, Dept. of Pathology and Cell BERNS, ANTON, Dept. of Molecular Genetics, The Biology, University Hospital of Iceland, Netherlands Cancer Institute, Amsterdam Reykjavik BI, WANLI, Dept. of Anatomy and Cell Biology, ARIGA, HIROYOSHI, Dept. of Molecular Biology, University of Cincinnati, Ohio Hokkaido University, Sapporo, Japan BIRAN, HAIM, Familial Cancer Program, Sheibe AURIGEMMA, ROSEMARIE, Dept. of Molecular Institute of Oncology, Kaplan Hospital, Re- Oncology, National Cancer Institute, Fred- hovot, Israel erick Cancer Research Facility, Frederick, BISHOP, J. MICHAEL, Dept. of Microbiology, Uni- Maryland versity of California, San Francisco AXELROD, AMY, Cell, Cambridge, Massachusetts BEACH, JAROMIR, Swiss Institute for Experimental AYTAY, SAIKA, Applied Genetics Laboratories, Cancer Research, Epalinges, Lausanne, Swit- Melbourne, Florida zerland BADE, ERNESTO, Dept. of Biology, University of BLAESE, MICHAEL, Dept. of Cell Immunology, Konstanz, Konstanz, Germany National Institutes of Health, Bethesda, BALMAIN, ALLAN, Dept. of Medical Oncology, Maryland Beatson Institute for Cancer Research, Glas- BLOOM, THEODORA, Current Biology, London, gow, Scotland, United Kingdom United Kingdom BAND,VIMLA, Dept. of Radiation Oncology, New BODRUG, SHARON,Div. of Oncogene and Tumor vi SYMPOSIUM PARTICIPANTS

Suppressor Gene Research, La Jolla Re- land Clinic Research Institute, Cleveland, search Foundation, La Jolla, California Ohio BOISE, LAWRENCE,Howard Hughes Medical Insti- CASTILLA, LUCIO, Dept. of Biology, University of tute, University of Chicago, Chicago, Illinois Michigan, Ann Arbor BOON, THIERRV, Ludwig Institute for Cancer Re- CERNI, CHRISTA, Dept. of Tumor Virology, Insti- search, Brussels, Belgium tute of Tumorbiology and Cancer Research, BORG,/~KE, Dept. of Oncology, University Hospi- University of Vienna, Austria tal, Lurid, Sweden CHAGNOVICH, DANIEL, Robert H. Lurie Cancer BOSSELUT, REMu Lab. of Viral and Cellular On- Center, Northwestern University, Chicago, cology, Institut Curie-Biology, Centre Uni- Illinois versitaire, Orsay, France CHANG, HENRY, Dept. of Molecular and Cell BOUCK, NOEL, Dept. of Microbiology and Immu- Biology, University of California, Berkeley nology, Northwestern University, Chicago, CHANG, KAI-HSUAN, Institute of Biotechnology, Illinois University of Texas Health Sciences Center, BOYLAN, JOHN, Du Pont Merck Pharmaceutical San Antonio Co., Wilmington, Delaware CHANG, SHENC-YUNG, Roche Molecular Systems, Alameda, California BRASH, DOUGLAS,Lab. of Radiobiology, Yale Uni- versity School of Medicine, New Haven, CHANG, ZEE-FEN, Dept. of Biochemistry, Chang Gung Medical College, Tao-Yuan, Taiwan Connecticut CHAPMAN, CAROLINE, Beatson Institute for Can- BRENNER, MALCOLM, Dept. of Bone Marrow cer Research, Glasgow, Scotland, United Transplantation, St. Jude Children's Re- Kingdom search Hospital, Memphis, Tennessee CHAY, CHRISTOPHER, Lab. of Human Carcino- Dept. of Biology, Massachu- BRISKEN, CATHERINE, genesis, National Cancer Institute, National setts Institute of Technology, Whitehead In- Institutes of Health, Bethesda, Maryland stitute for Biomedical Research, Cambridge, CHEN, CHANG-YAN, Cancer Research Center, Massachusetts Boston University School of Medicine, Bos- BROK-SIMONI, FRIDA, Institute of Hematology, ton, Massachusetts Chaim Sheba Medical Center, Tal Hash- CHEN, GANG, Institute of Biotechnology, Uni- omer, Israel versity of Texas Health Sciences Center, San BROWN, ANTHONY, Dept. of Cell Biology and Antonio Anatomy, Cornell University Medical Col- CHEN, YUMAY, Institute of Biotechnology, Uni- lege, New York, New York versity of Texas Health Sciences Center, San BROWNE, SARA, Dept. of Pathology and Micro- Antonio biology, University of Bristol, Bristol, COBRINIK, DAVID, Whitehead Institute for Bio- United Kingdom medical Research, Cambridge, Massachu- BRUSKIN, ARTHUR, Oncogene Science, Inc., setts Uniondale, New York COHEN, DALIA, Dept. of Oncology, Sandoz Re- BUSTELLO, XOSE, Dept. of Molecular Biology, search Institute, East Hanover, New Jersey Bristol-Myers Squibb Pharmaceutical Re- COHEN, ROBERT, Research Discovery, Genen- search Institute, Princeton, New Jersey tech, Inc., South San Francisco, California BUTLER, ALISON, Lab. of Molecular Endocrinolo- COLLINS, COLIN, Lawrence Berkeley National gy, Imperial Cancer Research Fund, Lon- Laboratory, University of California, San don, United Kingdom Francisco CALIGO, MARIAADELAIDE, Instituto Di Anatomia COLLINS, FRANCIS, Natl. Center for Human Patologica, Universit~i Di Pisa, Pisa, Italy Genome Research, National Institutes of CAMPBELL, BRUCE, Dept. of Molecular Biology, Health, Bethesda, Maryland Diagnostic Products Corp., Los Angeles, CORV, SUZANNE,Walter and Eliza Hall Institute California of Medical Research, Royal Melbourne CAMPISI, JUDITH, Dept. of Cell and Molecular Hospital, Victoria, Australia Biology, Lawrence Berkeley Laboratory, CoucH, FERGUS, Dept. of Internal Medicine, University of California, Berkeley University of Michigan, Ann Arbor CANTOR, GLENN, Dept. of Veterinary Microbiol- COULOMBE, JOSEE, Dept. of Biochemistry and ogy, Washington State University, Pullman Medicine, University of Ottawa, Ontario, CASEY, GRAHAM, Dept. of Cancer Biology, Cleve- Canada SYMPOSIUM PARTICIPANTS vii

CRISPIN, DAVID, Dept. of Gastroenterology, Uni- DOWDY, STEVEN, Whitehead Institute for Bio- versity of Washington, Seattle medical Research, Cambridge, Massachu- CRIST, KEITH, Medical College of Ohio, Toledo setts CROSBY, RENAL, Dept. of Cell Biology and DOWNES, STEPHEN, Dept. of , University Medicinal Chemistry, Glaxo Research Insti- of Cambridge, Cambridge, United Kingdom tute, Research Triangle Park, North DRABKIN, HARRY, Dept. of Medical Oncology, Carolina University of Colorado Health Sciences CUI, WEI, Dept. of Medical Genetics, University Center, Denver of Glasgow, Scotland, United Kingdom DRAETrA, GIULIO, Dept. of Biological Research, CULVER, KENNETH, Iowa Methodist Medical Cen- Mitotix, Inc., Cambridge, Massachusetts ter, Human Gene Therapy Research Insti- DUROCHER, FRANCINE, Dept. of Molecular Endo- tute, Des Moines, Iowa crinology, CHUL Research Center, Quebec, D'ANDREA, ALAN, Div. of Pediatric Oncology, Canada Dana-Farber Cancer Institute, Boston, EBLEN, SCOTT, Dept. of Thoracic Research, Mayo Massachusetts Clinic, Rochester, Minnesota DAI, KANG, Institute of Biotechnology, Universi- EISENMAN, ROBERT, Div. of Basic Sciences, Fred ty of Texas Health Sciences Center, San Hutchinson Cancer Research Center, Seat- Antonio tle, Washington DALBAGNI, GUIDO, Dept. of Urology, Memorial EVAN, GERARD, Lab. of Biochemistry of the Cell Sloan-Kettering Cancer Center, New York, Nucleus, Imperial Cancer Research Fund, New York London, United Kingdom DALLA-FAVERA, RICCARDO, Dept. of Pathology, FEARON, ERIC, Boyer Center for Molecular Medi- Columbia University College of Physicians cine, Yale University School of Medicine, & Surgeons, New York, New York New Haven, Connecticut DAS, GOKUL, Dept. of Molecular Biology, Uni- FEINBERG, ANDREW, Dept. of Medicine and Mo- versity of Texas Health Center, Tyler lecular Biology and Genetics, Johns Hop- DEBANT, ANNE, Dept. of Tumor Immunology, kins University School of Medicine, Balti- Dana-Farber Cancer Institute, Boston, more, Maryland Massachusetts DE BRUIJN, DIEDERIK, Dept. of Human Genetics, FILATOV, LEONID, Dept. of Pathology, St Jude University of Nijmegen, The Netherlands Children's Research Hospital, Memphis, DEICHMAN, ALEXANDER MAZKOVICH, Lab. for Tennessee Experiments in Diagnosis and Therapy of FLAVELL, RICHARD, Sect. of Immunobiology, Yale Tumors, Oncology Center, Moscow, Russia University, New Haven, Connecticut DE LEEUW, BERTIE, Dept. of Human Genetics, FLICK, PARKE, United States Biochemical Corpo- University Hospital, University of Nijmegen, ration, Cleveland, Ohio The Netherlands FOLKMAN, JUDAH, Dept. of Surgery and Surgical DEVEREUX, THEODORA, Lab. of Molecular Car- Research, Children's Hospital, Harvard Uni- cinogenesis, NIH-National Institute of En- versity Medical School, Boston, Massachu- vironmental Health Sciences, Research Tri- setts angle Park, North Carolina FOULKES, J. GORDON, Oncogene Science, Inc., DIAMANDIS, ELEFTHERIOS, Dept. of Clinical BiD- Uniondale, New York chemistry, Toronto Hospital, Toronto, On- FREDERICKS,WILLIAM, The Wistar Institute, Phila- tario, Canada delphia, Pennsylvania DIERKS, MEGHAN, Dept. of Surgery, Washington FREIJE, DIHA, Dept. of Genetics, Boyer Center University School of Medicine, St. Louis, for Molecular Medicine, Yale University, Missouri New Haven, Connecticut DONEHOWER, LAWRENCE,Dept. of Molecular Vir- FRIEDMAN, LORI, Dept. of Molecular and Cell ology, Baylor College of Medicine, Houston, Biology, University of California, Berkeley Texas FRIEND, STEPHEN, Massachusetts General Hospi- DOSHI, ASHITA, Dept. of Molecular Biology and tal Cancer Center, Charlestown, Massachu- Microbiology, Tufts University School of setts Medicine, Boston, Massachusetts FRISCHAUF, ANNA-MARIA, Imperial Cancer Re- DovE, WILLIAM,McArdle Laboratory for Cancer search Fund, London, United Kingdom Research, University of Wisconsin, Madison FUJITA, DONALD, Dept. of Medical Biochemistry, viii SYMPOSIUM PARTICIPANTS

University of Calgary Medical Center, Cal- icine, John Radcliffe Hospital, Headington, gary, Alberta, Canada Oxford, United Kingdom FURNEAUX, HENRY, Dept. of Pharmacology and GOONEWARDENA, PONMANI, Dept. of Genetics, Therapeutics, Memorial Sloan-Kettering Kaiser Medical Center, San Jose, California Cancer Center, New York, New York GORBOVITSKAYA, MARY, Dept. of Genetics and FURTH, MARK, Dept. of Molecular Sciences, Selection, St. Petersburg University, St. Glaxo Research Institute, Research Triangle Petersburg, Russia Park, North Carolina GOROSPE, MYRIAM, Gerontology Research Cen- FUTREAL, ANDY, Lab. of Molecular Carcinogen- ter, National Institute on Aging, National esis, NIH-National Institute of Environmen- Institutes of Health, Baltimore, Maryland tal Health Sciences, Research Triangle Park, GOTTESMAN, MICHAEL, Dept. of Molecular Biolo- North Carolina gy, National Cancer Institute, National Insti- GABRIELSEN, ODD, Dept. of Biochemistry, Uni- tutes of Health, Bethesda, Maryland versity of Oslo, Norway GRAY, JOSEPH, Dept. of Cytometry, University of GALLOWAY, DENISE, Fred Hutchinson Cancer California, San Francisco Research Center, Seattle, Washington GREEN, MAURICE, Dept. of Molecular Virology, GAO, CHUAN, Lab. of Urology Research, Uni- St. Louis University Medical Center, St. versity of Texas M.D. Anderson Cancer Louis, Missouri Center, Houston GRETARSDOVnR, SOLVEIG, Lab. of Molecular and GEBHARDT, MARK, Dept. of Orthopedic Surgery, Cell Biology Research, Icelandic Cancer Massachusetts General Hospital, Boston, Society, Reykjavik Massachusetts GREULICH, HEIDI, Lab. of Molecular Oncology, GEMMILL, ROBERT, Eleanor Roosevelt Institute, Rockefeller University, New York, New Denver, Colorado York GERMAN, JAMES, New York Blood Center, New GRONER, BERND, Tumor Biology Center, Insti- York, New York tute for Experimental Cancer Research, GERONDAKIS, STEVE, Walter and Eliza Hall Insti- Freiburg, Germany tute of Medical Research, Royal Melbourne GUALBERTO, ANTONIO, Lineberger Comprehen- Hospital, Victoria, Australia sive Cancer Center, University of North GESSLER, MANFRED, Dept. Physiologische Carolina, Chapel Hill Chemie, Biozentrum der Universit~it GUPTA, SOHAN, Hipple Cancer Research Center, Wtirtzburg, Wtirtzburg, Germany Dayton, Ohio GIAM, CHoU-ZEN, Dept. of Infectious Diseases, HABER, DANIEL, Massachusetts General Hospital Case Western Reserve University School of Cancer Center, Charlestown, Massachusetts Medicine, Cleveland, Ohio HAKIMI, JANETTE, Dept. of Urology, Johns Hop- GmsoN, NEIL, Dept. of Neuroscience and Cancer, kins University School of Medicine, Balti- Pfizer, Groton, Connecticut more, Maryland GIDEON, RECHAVI, Institute of Hematology, HALL, FREDERICK, Dept. of Orthopedic Surgery, Chaim Sheba Medical Center, Tel Childrens Hospital of Los Angeles, Uni- Hashomer, Israel versity of Southern California, Los Angeles GIL-GOMEZ, GABRIEL, Dept. of Biochemistry, HALL, KEARA, National Cell and Tissue Culture University of Barcelona, Barcelona, Spain Centre, Dublin City University, Glasnevin, GILLE, HENDRIK, Spemann Lab., Max-Planck-In- Dublin, Ireland stitut fiJr Immunbiologie, Freiburg, Ger- HALL, STEPHEN, Brooklyn, New York many HANAHAN, DOUGLAS, Dept. of Biochemistry, GILLILAND, GARY, Dept. of Medicine, Brigham Hormone Research Institute, University of and Women's Hospital, Harvard Medical California, San Francisco School, Boston, Massachusetts HANLEY-HYDE, JOAN, Lab. of Genetics, National GOOLEY, LUCY, National Cancer Institute, Na- Cancer Institute, National Institutes of tional Institutes of Health, Bethesda, Mary- Health, Bethesda, Maryland land HANNINK, MARK, Dept. of Biochemistry, Uni- GOLUB, TODD, Dept. of Medicine, Brigham and versity of Missouri, Columbia Women's Hospital, Harvard Medical School, HANSEN, LISE LOTTE, Dept. of Human Genetics, Boston, Massachusetts Aarhus University, Aarhus, Denmark GOODFELLOW, HU~H, Institute of Molecular Med- HARADA, HISASHI, Institute for Molecular and SYMPOSIUM PARTICIPANTS ix

Cell Biology, Osaka University, Osaka, HUANG, DOLLY, Dept. of Pathology, Chinese Uni- Japan versity of Hong Kong, Shatin HARLEY, CALVIN, Geron Corp., Menlo Park, HUANG, MARY, Dept. of Pathology and Immunol- California ogy, Tufts University, Dana-Farber Cancer HARLOW, ED, Massachusetts General Hospital Institute-Children's Hospital, Boston, Mas- Cancer Center, Charlestown, Massachusetts sachusetts HARON, JAY, Dept. of Biotech Research and HUDSON, KEVIN, Dept. of Cancer Research, Development, R.W. Johnson Pharmacology Zeneca Pharmaceuticals, Macclesfield, Che- Research Institute, San Diego, California shire, United Kingdom HARPER, WADE, Dept. of Biochemistry, Baylor HUFF, ANNE, Sterling Winthrop, Inc., College- College of Medicine, Houston, Texas ville, Pennsylvania HARRIS, CURTIS, Lab. of Human Carcinogenesis, HUNG, PAUL, Dept. of Papillomavirus Research, National Cancer Institute, Bethesda, Mary- Wyeth-Ayerst Research, Radnor, Pennsyl- land vania HARTER, NIKKI, Dept. of Molecular Biology, IGGO, RICHARD, Swiss Institute for Experimental Cleveland Clinic Foundation, Cleveland, Cancer Research, Epalinges, Switzerland Ohio IRIE, SHINJI, La Jolla Cancer Research Founda- HARTWELL, LELAND, Dept. of Genetics, Universi- tion, La Jolla, California ty of Washington, Seattle ISAACS, WILLIAM, Dept. of Urology, Johns Hop- HARVEY, RICHARD, Dept. of Research Develop- kins University School of Medicine, Balti- ment, Gen-Probe, San Diego, California more, Maryland HATA, AKIKO, Dept. of Molecular Oncology, ISHIKAWA, TOSHIHISA, Dept. of Experimental Rockefeller University, New York, New Pediatrics, University of Texas M.D. Ander- York son Cancer Center, Houston HEGI, MONIKA,Institute of Neuropathology, Uni- ISHIZAKA, YUKIHITO, Dept. of Molecular Biology, versity Hospital, Zurich, Switzerland The Cleveland Clinic Foundation, Cleveland, HENGST, LUDGER, Dept. of Molecular Biology, Ohio Scripps Research Institute, La Jolla, Califor- JACKS, TYLER, Center for Cancer Research, nia Massachusetts Institute of Technology, Cam- HEO, DAE, MSRBI, University of Michigan, Ann bridge, Massachusetts Arbor JACOB, WILLIAM, Genetic Tharapy, Inc., Gaithers- HERZOG, CHRISTOPHER, Dept. of Pathology, burg, Maryland Medical College of Ohio, Toledo JAKOBS, RAINER, German Cancer Research Cen- HILBERG, FRANK, Bender and Co., Ernst-Boeh- ter (DKFZ), Heidelberg, Germany ringer-Institut, Vienna, Austria JAMES, GUY, Dept. of Molecular Genetics, Uni- HOEIJMAKERS, JAN, Dept. of Cell Biology and versity of Texas Southwest Medical Center, Genetics, Erasmus University, Rotterdam, Dallas The Netherlands JARAMILLO,MARIA, Dept. of Medicine, University HOGGARD, NIGEL, Dept. of Cancer Genetics, of Ottawa, Ontario, Canada Paterson Institute for Cancer Research, JOHANNSSON, OSKAR THOR, Dept. of Oncology, Manchester, United Kingdom University Hospital, Lund, Sweden HORVlTZ, U. ROBERT, Dept. of Biology, Howard JOHNSON, EDWARD, Dept. of Pathology, Mount Hughes Medical Institute, Massachusetts Sinai School of Medicine, New York, New Institute of Technology, Cambridge, Massa- York chusetts JOHNSON, LEISA, Center for Cancer Research, HOSTOMSKA, ZUZANA, Dept. of Biochemistry, Massachusetts Institute of Technology, Cam- Agouron Pharmaceuticals, Inc., San Diego, bridge, Massachusetts California KAHN, SCOTT, Institute for Cancer Research, HOUSMAN, DAVID, Center for Cancer Research, Columbia University, New York, New York Massachusetts Institute of Technology, KAMB, ALEXANDER, Dept. of Genomics, Myriad Cambridge, Massachusetts Genetics, Inc., Salt Lake City, Utah HOWLEY, PETER, Dept. of Pathology, Harvard KASTAN, MICHAEL, Dept. of Oncology, Johns Medical School, Boston, Massachusetts Hopkins University School of Medicine, HSIEH, LING-LING,Dept. of Public Health, Chang- Baltimore, Maryland Gung Medical College, Tao-Yuan, Taiwan KELLY, THOMAS, Dept. of Molecular Biology and x SYMPOSIUM PARTICIPANTS

Genetics, Johns Hopkins University School LADANYI, MARC, Dept. of Pathology, Memorial of Medicine, Baltimore, Maryland Sloan-Kettering Cancer Center, New York, KELMAN, ZVI, Dept. of Microbiology, Cornell New York University Medical Center, New York, New LAND, HARTMUT,Imperial Cancer Research Fund, York London, United Kingdom KERBEL, ROBERT, Sunnybrook Health Science LANDERS, JOHN, Dept. of Genetics, University of Center, University of Toronto, Ontario, Pennsylvania, Philadelphia Canada LANE, DAVID, Dept. of Biochemistry, Cancer Re- KIBERSTIS, PAULA, Science, Washington, D.C. search Campaign Laboratories, University of KING, MARY-CLAIRE, Epidemiology Program, Dundee, Scotland, United Kingdom School of Public Health, University of Cali- LEE, AMANDA, Dept. of Cell Biology, Glaxo Re- fornia, Berkeley search Institute, Durham, North Carolina KINSELLA, ANNE, Dept. of Surgery, Royal Liver- LEE, EVA Y.-H.P., Dept. of Biotechnology, Uni- pool University Hospital, University of versity of Texas Health Sciences Center, San Liverpool, United Kingdom Antonio KIPREOS, EDWARD, Dept. of Biology, Johns Hop- LEE, STEPHEN, Dept. of Pathology, Washington kins University, Baltimore, Maryland University School of Medicine, St. Louis, KIRSCH, ILAN, Navy Medical Oncology Branch, Missouri National Cancer Institute, National Institutes LEE, WEN-HWA, Institute of Biotechnology, Uni- of Health, Bethesda, Maryland versity of Texas Health Sciences Center, San KITAJEWSKI, JAN, Dept. of Pathology, Columbia Antonio University College of Physicians & Surgeons, LEMOINE, NICHOLAS, Oncology Unit, Hammer- New York, New York smith Hospital, Imperial Cancer Research Ko, TIEN, Dept. of Surgery, University of Texas Fund, London, United Kingdom Medical Branch, Galveston LEUTZ, ACHIM, Zentrum ffir Molekulare Biologie, KOIKE, KATSURO, Cancer Institute of Japan, University of Heidelberg, Germany Tokyo KOLODNER, RICHARD, Dana-Farber Cancer Insti- LEVINE, ARNOLD, Dept. of Molecular Biology, tute, Harvard Medical School, Boston, Princeton University, Princeton, New Jersey Massachusetts LI, JIAN, Dept. of Molecular and Experimental KORSMEYER, STANLEY, Howard Hughes Medical Medicine, Scripps Research Institute, La Institute, Washington University School of Jolla, California Medicine, St. Louis, Missouri LI, WAN-CHENG,Dept. of Ophthalmology, Colum- KosKx, RAYMOND, Old Lyme, Connecticut bia University, New York, New York KRASIKOV, NATALIE, Integrated Genetics, Santa LIN, RONG TUAN,Lady Davis Institute for Medical Fe, New Mexico Research, Montreal, Quebec, Canada KRONER, GABRIELE,Institute of Molecular Biolo- LIN, SHENCAI,Dept. of Medicine, Howard Hughes gy, University of Essen Medical School, Medical Institute, University of California at Essen, Germany San Diego, La Jolla KRTOLICA, ANA, Dept. of Biochemistry, Universi- LING, VICTOR, The Ontario Cancer Institute, ty of Rochester Medical Center, Rochester, Toronto, Ontario, Canada New York LISITSYN, NIKOLAI, Cold Spring Harbor Labora- KRUSE, ULRICH, Dept. of Molecular and Ex- tory, Cold Spring Harbor, New York perimental Medicine, Scripps Research Insti- LIU, WEI, Dept. of Cell and Molecular Biology, tute, La Jolla, California Dana-Farber Cancer Institute, Boston, KRUZELOCK, RUSSELL,Dept. of Molecular Genet- Massachusetts ics, University of Texas M.D. Anderson Can- LIU, XIAO-LONG, Dept. of Radiation Oncology, cer Center, Houston New England Medical Center, Boston, KUNG, HSING-JIEN, Dept. of Molecular Biology Massachusetts and Microbiology, Case Western Reserve LIU, YUSEN, Gerontology Research Center, Na- University, Cleveland, Ohio tional Institute on Aging, Baltimore, Mary- KURTZ, DAVID, Dept. of Pharmacology, Medical land University of South Carolina, Charleston LIVINGSTON, DAVID, Dept. of Neoplastic Disease KWON, Ho JEONG, Dept. of Agricultural Chemis- Mechanisms, Dana-Farber Cancer Institute, try, University of Tokyo, Japan Boston, Massachusetts SYMPOSIUM PARTICIPANTS xi

LOEWENSTEIN, PAUL, Dept. of Molecular Virology, MERAJVER, SOFIA, Dept. of Internal Medicine, Health Science Center, St. Louis University, University of Michigan, Ann Arbor St. Louis, Missouri MERLO, GIORGIO, Friedrich Miescher Institute, LUDLOW,JOHN, Dept. of Tumor Biology, Universi- Basel, Switzerland ty of Rochester, Rochester, New York MILLER, JULIA, Dept. of Research and Develop- LUNDGREN, KAREN, Dept. of Pharmacology, ment, Gen-Probe, Inc., San Diego, California Glaxo Research Institute, Research Triangle MINNA, JOHN, Simmons Cancer Center, University Park, North Carolina of Texas Southwestern Medical School, Dal- LUTCHMAN, MOHINI, Dept. of Neuroscience, las McGill University, Montreal, Quebec, MITCHELL, LLOYD, Dept. of Pathology, George Canada Washington University, Washington, D.C. LUTZGER, STUART, Dept. of Molecular Biology, MIZUKAMI, TAMIO, Tokyo Research Laboratories, Princeton University, Princeton, New Jersey Kyowa Hakko Kogyo Co., Ltd., Tokyo, MA, CHI, Metabolism Branch, National Cancer Japan Institute, National Institutes of Health, MOELLING, KARIN, Institute of Medical Virology, Bethesda, Maryland University of Zurich, Switzerland MACKENZIE, KAREN, Dept. of Clinical Phar- MOLL, UTE, Dept. of Pathology, State University macology, St.Vincent's Hospital, Rushcutters of New York, Stony Brook Bay, New South Wales, Australia MONDELLO, CHIARA, Istituto Di Genetica Bio- MACLEOD, KAY, Center for Cancer Research, chimica ed Evoluzionistica, Consiglio Massachusetts Institute of Technology, Cam- Nazionale Delle Ricerche, Padua, Italy bridge, Massachusetts MOREIRA, ANTONIO, Dept. of Genetics, Univer- MAI, SABINE, Basel Institute for Immunology, sidade Nova de Lisboa, Lisbon, Portugal Basel, Switzerland MOROY, TARIK, Molekularbiologie und Tumor- MAIHLE, NITA, Dept. of Biochemistry and Molec- forschung, Phillips Universit~t Marburg, ular Biology, Mayo Clinic, Rochester, Min- Marburg, Germany nesota MOSHINSKY,DEBORAH, Div. of Toxicology, Massa- MAK, YIN, Dept. of Cancer Studies, CRC Lab- chusetts Institute of Technology, Cambridge, oratories, University of Birmingham Medical Massachusetts School, Birmingham, United Kingdom MANOHAR, CHITRA,Robert H. Lurie Cancer Cen- MoussEs, SPYRO, Dept. of Molecular and Medical ter, Northwestern University, Chicago, Il- Genetics, Samuel Lunenfeld Institute, Mount linois Sinai Hospital, Toronto, Ontario, Canada MANSOUR, SAM, Dept. of Chemistry and Biochem- MOYNAHAN, MARYELLEN,Dept. of Medicine, Cell istry, University of Colorado, Boulder Biology and Genetics, Memorial Sloan-Ket- MARTIN, GERALD, Dept. of Radiation Oncology, tering Cancer Center, New York, New York Glasgow University, Glasgow, Scotland, MOLLER, ROLF, Institut ftir Molekularbiologie und United Kingdom Tumorforschung, Phillips Universitfit Mar- MARX, JEAN, Science, Washington, D.C. burg, Marburg, Germany MARX, MARIA, Dept. of Retroviral and Molecular MUTHUSWAMY,SENTHIL, Dept. of Molecular Biolo- Oncology, Institut Curie-Biology, Centre gy and Biotechnology, McMaster University, Universitaire, Orsay, France Hamilton, Ontario, Canada MARX, STEPHEN, Sect. of Genetics and Endo- NABEL, GARY, Dept. of Internal Medicine, How- crinology, National Institutes of Health, ard Hughes Medical Institute, University of Bethesda, Maryland Michigan, Ann Arbor MAVROTHALASSITIS, GEORGIOS, Lab. of Molecular NASI, SERGIO, Centro Acidi Nucleici, Universith Oncology, National Cancer Institute, Fred- La Sapienza, Rome, Italy erick, Maryland NATHANS, DANIEL, Dept. of Molecular Biology MCALOON, ELIZABETH, Chadbourne and Parke, and Genetics, Johns Hopkins University, New York, New York Baltimore, Maryland MCCORMICK, FRANK, ONYX Pharmaceutical NAUMANN, ULRIKE, Institut ftir Strahlen und Corp., Richmond, California Zellforschung, Universit/it Wurzburg, Ger- MCMAHON, JERRY, Sugen, Inc., Redwood City, many California NEIMAN, PAUL,Div. of Basic Science, Fred Hutch- xii SYMPOSIUM PARTICIPANTS

inson Cancer Research Center, Seattle, PELTOKETO, HELLEW, Biocenter and Dept. of Washington Clinical Chemistry, University of Oulu, Fin- NGAN, BO, Dept. of Pathology, Sunnybrook land Health Science Centre, University of PEREIRA-SMITH, OLIVIA,Dept. of Molecular Virol- Toronto, Ontario, Canada ogy, Huffington Center on Aging, Baylor NOMURA, HITOSHI, Dept. of Molecular Science, College of Medicine, Houston, Texas Chugai Pharmaceutical Co., Ltd., Shizuoke, PERLMAN, RIKI,Whitehead Institute for Biomedi- Japan cal Research, Cambridge, Massachusetts NORDHEIM, ALFRED,Institute for Molecular Biolo- PERUCHO, MANUEL, California Institute of Bio- gy, Hannover Medical School, Hannover, logical Research, La Jolla, California Germany PETERS, GORDON, St. Bartholomew's Hospital, NUCIFORA, GIUSEPPINA, Dept. of Medicine, Uni- Imperial Cancer Research Fund, London, versity of Chicago, Chicago, Illinois United Kingdom O'CONNOR, PATRICK,Dept. of Molecular Pharma- PETRITSCH, CLAUDIA, Dept. of Pathology, Insti- cology, National Cancer Institute, Bethes- tute of Molecular Pathology, Vienna, Aus- da, Maryland tria O'NEILL, EDWARD,Dept. of Molecular Immunol- ogy, Merck, Sharp, & Dohme Research Lab- PHILIPP, ANGELIKA, Zentrum ftir Molekulare oratories, Rahway, New Jersey Biologie (ZMBH), Heidelberg, Germany ONEL, KENAN, Dept. of Microbiology, Cornell PINTZAS, ALEXANDER, Institut de Chimie University Medical College, New York, New Biologique, Faculte Medicin, CNRS-LGME, York INSERM, Strasbourg, France OREN, MOSnE, Dept. of Chemical Immunology, PIPAS, JAMES, Dept. of Biological Sciences, Uni- Weizmann Institute of Science, Rehovot, Is- versity of Pittsburgh, Pittsburgh, Pennsyl- rael vania ORTH-TAusSIG, KIM, Dept. of Biochemistry, Uni- PRENDERGAST,GEORGE, The Wistar Institute, Phil- versity of Texas Southwestern Medical Cen- adelphia, Pennsylvania ter, Dallas, Texas PRESTON, GLORIA, Lab. of Molecular Carcinogen- OSTERMEYER, ELIZABETH,Dept. of Molecular and esis, NIH-National Institute of Environmen- Cell Biology, University of California, Berke- tal Health Sciences, Research Triangle Park, ley North Carolina OSTMAN, ARNE, Biomedical Center, Ludwig Insti- PRIVES, CAROL, Dept. of Biological Sciences, tute for Cancer Research, Uppsala, Sweden Columbia University, New York, New York OZffELIK, HILMI, Dept. of Molecular and Medical QIN, XIAOFENG, Lab. of Molecular Immunology, Genetics, Samuel Lunenfeld Institute, Mount Rockefeller University, New York, New Sinai Hospital, Toronto, Ontario, Canada York OZER, HARVEY,Dept. of Microbiology and Molec- RADFORD, DIANE, Washington University School ular Genetics, UMDNJ-New Jersey Medical of Medicine, St. Louis, Missouri School, Newark, New Jersey RANZANI, G.N., Dept. of Genetics and Microbiol- PADILLA, DAVID, Amgen, Inc., Thousand Oaks, ogy, University of Padua, Italy California RAO, NAGARAJA, Dept. of Cancer Research, Eli PANDITA, TEJ, Center for Radiological Research, Lilly & Company, Indianapolis, Indiana Columbia University, New York, New York PATY, PHILLIP,Dept. of Surgery, Memorial Sloan- RAULF, FRIEDRICH,Dept. of Preclinical Research, Kettering Cancer Center, New York, New Sandoz Pharma, Ltd., Basel, Switzerland York RAUSCHER, FRANK, The Wistar Institute, Philadel- PAVLETICH,NIKOLA, Dept. of Cellular Biochemis- phia, Pennsylvania try and Biophysics, Memorial Sloan-Ketter- REICH, NANCY, Dept. of Pathology, State Uni- ing Cancer Center, New York, New York versity of New York, Stony Brook PAWELEK, JOHN, Dept. of Dermatology, Yale Uni- REID, BR1AN, Div. of Gastroenterology, Universi- versity School of Medicine, New Haven, ty of Washington, Seattle Connecticut RINKER-SCHAEFFER, CARRIE, Oncology Center, PELLS, STEPHEN, Dept. of Pathology, The Uni- Johns Hopkins University School of Medi- versity of Edinburgh Medical School, Scot- cine, Baltimore, Maryland land, United Kingdom ROBERTS, JAMES, Dept. of Basic Sciences, Fred SYMPOSIUM PARTICIPANTS xiii

Hutchinson Cancer Center, Seattle, Wash- SCUDERI, RICHARD,Lab. of Hematology, Karolin- ington ska Hospital, Stockholm, Sweden ROGLER, CHARLES, Dept. of Medicine, Liver Re- SEIZINOER, BERND, Dept. of Oncology Drug Re- search Center, Albert Einstein College of search, Bristol-Myers Squibb Pharmaceutical Medicine, Bronx, New York Research Institute, Princeton, New Jersey ROHN, JENNIFER, Dept. of Microbiology, Universi- SENGSTAG, CHRISTIAN, Institute of Toxicology, ty of Washington, Seattle Swiss Federal Institute of Technology and RON, DAVID, Dept. of Medical and Cell Biology, University of Zurich, Schwerzenbach, Swit- New York University Medical Center, New zerland York, New York SETH, ARUN, Lab. of Molecular Oncology, Nation- ROWLEY, JANET, Dept. of Medicine, University of al Cancer Institute, Frederick Cancer Chicago, Chicago, Illinois Research and Development Center, Fred- ROYER-POKORA, BRIGITTE, Institute of Human erick, Maryland Genetics, University of Heidelberg, Ger- SETO, MASAO, Lab. of Chemotherapy, Aichi Can- many cer Center Research Institute, Nagoya, Japan SABE, HISATAKA, Dept. of Biological Responses, SETTLEMAN, JEFFREY, Dept. of Medicine, Harvard Institute for Viral Research, Kyoto Universi- Medical School, Massachusetts General ty, Kyoto, Japan Hospital Cancer Center, Charlestown, SABERS, CANDACE,Dept. of Pharmacology, Mayo Massachusetts Clinic, Rochester, Minnesota SGOURAS, DIONYSSIOS, National Cancer Institute, National Institutes of Health, Frederick Can- SAGER, RUTH, Dept. of Cancer Genetics, Dana- cer Research and Development Center, Fre- Farber Cancer Institute, Boston, Massachu- derick, Maryland setts SHAN, BEI, Institute of Biotechnology, University SAMBROOK, JOSEPH, Dept. of Biochemistry, Uni- of Texas Health Sciences Center, San An- versity of Texas Southwestern Medical Cen- tonio ter, Dallas SHARP, STEPHEN, Dept. of Biological Sciences, SANDBERG NORDQVIST, ANN-CHRISTIN, Dept. of R.W. Johnson Pharmaceutical Research In- Oncology-Pathology, Karolinska Hospital, stitute, San Diego, California Stockholm, Sweden SHEA, MARY JOAN, Oyster Bay Cove, New York SANDS, ARTHUR, Dept. of Molecular Genetics, SHELLING, ANDREW, Institute of Molecular Medi- Baylor College of Medicine, Houston, Texas cine, John Radcliffe Hospital, Imperial Can- SARDET, CLAUDE, Whitehead Institute for Bio- cer Research Fund, Oxford, United Kingdom medical Research, Cambridge, Massachu- SHERR, CHARLES, Dept of Tumor Biology, How- setts ard Hughes Medical Institute, St. Jude Chil- SCHERNECK, SmGFRIED, Dept. of Tumor Genetics, dren's Research Hospital, Memphis, Tennes- Max Delbrfick Center for Molecular Medi- see cine, Berlin SHORT, NICHOLAS,Nature, London, United King- SCHIMKE, ROBERT, Dept. of Biological Sciences, dom School of Medicine, SIMARD, JACQUES, Dept. of Molecular Endocrinol- Stanford, California ogy, CHUL Research Center, Laval Uni- SCHLEGEL, RICHARD, Dept. of Pathology, versity, Quebec, Canada Georgetown University Medical Center, SINGH, BALRAJ, Dept. of Molecular Pathology, Washington, D.C. University of Texas M.D. Anderson Cancer SCHLEGEL, ROBERT, Lab. of Toxicology, Harvard Center, Houston School of Public Health, Boston, Massachu- SKLAR, JEFFREY, Dept. of Pathology, Brigham and setts Women's Hospital, Harvard Medical School, SCHLESSINGER, JOSEPH, Dept. of Pharmacology, Boston, Massachusetts New York University Medical Center, New SKOLNICK, MARK, Dept. of Genetic Epidemiology, York, New York University of Utah, Salt Lake City SCHOENBERG, MARK, Dept. of Urology, Johns SKOULTCHI, ARTHUR, Dept. of Cell Biology, Al- Hopkins Hospital, Baltimore, Maryland bert Einstein College of Medicine, Bronx, SCHOTT, DAVID,Geraldine Brush Cancer Research New York Institute, San Francisco, California SLAMON,DENNIS, Dept. of Hematology/Oncology, xiv SYMPOSIUM PARTICIPANTS

University of California School of Medicine, TARUSCIO, DOMENICA, Ultrastructures, Istituto Los Angeles Superiore de Sanita, Rome, Italy SMALL, MICHAEL, Dept. of Microbiology, New TAVASSOLI, MAHVASH, Dept. of Genetics and De- Jersey Medical School, Newark, New Jersey velopment, University of Sussex School of SPAARGAREN, MARCEL, ONYX Pharmaceutical Biological Sciences, Brighton, West Sussex, Corp., Richmond, California United Kingdom STACEY, DENNIS, Dept. of Molecular Biology, The TAYA, YOICHI, National Cancer Center Research Cleveland Clinic Foundation, Cleveland, Institute, Tokyo, Japan Ohio TEPPER, ROBERT,Dept. of Tumor Biology, Massa- STACK, MARIA, Dept. of Cancer Genetics, Pater- chusetts General Hospital, Charlestown, son Institute for Cancer Research, Manches- Massachusetts ter, United Kingdom THEILLET, CHARLES, Dept. of Molecular Biology, STAMPFER, MARTHA, Dept. of Cell and Molecular CNRS, University of Montpellier, Montpel- Biology, University of California, Berkeley lier, France STANBRIDGE, ERIC, Dept. of Microbiology and Molecular Genetics, University of California, THOMAS, GILLES, Lab. of Tumor Genetics, Institut Irvine Curie, Paris, France STAUDT, LOUIS, Metabolism Branch, National THOME, KELLY, Dept. of Pathology, Tufts Uni- Cancer Institute, National Institutes of versity School of Medicine, Boston, Massa- Health, Bethesda, Maryland chusetts STAWICKI, MARY, Sterling Winthrop, Inc., Col- THORLACIUS, STEINUNN, Lab. of Molecular and legeville, Pennsylvania Cell Biology Research, Icelandic Cancer STEPHENSON, JOHN, Santa Cruz Biotechnology, Society, Reykjavik Inc., Santa Cruz, California THORNTON, GEORGE, Dept. of Biological Sciences, STERNBERG, PAUL, Dept. of Biology, California R.W. Johnson Pharmaceutical Research In- Institute of Technology, Pasadena, California stitute, San Diego, California STILLMAN, BRUCE, Cold Spring Harbor Labora- TIKHONENKO, ANDREI, Dept. of Basic Sciences, tory, Cold Spring Harbor, New York Fred Hutchinson Cancer Research Center, STUBDAL, HILDE, Dana-Farber Cancer Institute, Seattle, Washington Boston, Massachusetts TESTY, THEA,Dept. of Pathology, Lineberger Can- Su, WEN, Dept. of Cell and Molecular Biology, cer Research Center, University of North Dana-Farber Cancer Institute, Boston, Carolina, Chapel Hill Massachusetts TONIN, PATRICIA,Dept. of Medicine, McGill Cen- Su, YAN, Lab. for Cancer Genetics, Natl. Center ter for Human Genetics, Montreal, Quebec, for Human Genome Research, National In- Canada stitutes of Health, Bethesda, Maryland TOPOL, LILIA, Dept. of Molecular Oncology, SUPER, HEIDI GILL, Dept. of Molecular Genetics Frederick Cancer Research Facility, Fred- and Cell Biology, University of Chicago, erick, Maryland Chicago, Illinois TOUMBIS, CONSTANTINE, Dept. of Cell Biology, Dept. of Pathology, SWIRNOFF, ALEXANDER, Albert Einstein College of Medicine, Bronx, Washington University School of Medicine, New York St. Louis, Missouri SZEKELY, LASZLO,Microbiology and Tumor Biolo- TSAI, MIAW-SHEUE,Dept. of Biological Chemistry, gy Center, Karolinska Institute, Stockholm, University of California School of Medicine, Sweden Davis TAKENAKA, IVONE, Dept. of Molecular Genetics TUREK, LUBOMIR, Dept. of Pathology, University and Cell Biology, Bristol-Myers Squibb Phar- of Iowa College of Medicine, Iowa City maceutical Research Institute, Princeton, VALANCIUS-MANGEL, VICKY, Dept. of Molecular New Jersey Genetics, University of Cincinnati, Cincin- TAKIMOTO, MASATO,Dept. of Molecular and Cel- nati, Ohio lular Biology, Osaka University, Osaka, VANDE WOUDE, GEORGE, Lab. of Molecular On- Japan cology, ABL-Basic Research Program, NCI- TAM, WAYNE, Dept. of Molecular Biology, Me- Frederick Cancer Research and Develop- morial Sloan-Kettering Cancer Institute, ment Center, Frederick, Maryland New York, New York VAN DYKE, TERRY, Dept. of Biochemistry and SYMPOSIUM PARTICIPANTS xv

Biophysics, University of North Carolina, esis, NIH-National Institute of Environmen- Chapel Hill tal Health Sciences, Research Triangle Park, VAN MEIR, ERWIN, Ludwig Institute for Cancer North Carolina Research, La Jolla, California WITTE, OWEN, Howard Hughes Medical Institute, VAN ZEIJL, MARJA, Dept. of Molecular Biology, University of California, Los Angeles American Cyanamid Company, Pearl River, WOOD, ALEXANDER,Dept. of Oncology and Virol- New York ogy, Hoffmann-LaRoche, Inc., Nutley, New VARMA, VIJAY, Dept. of Pathology, Atlanta VA Jersey Medical Center, Decatur, Georgia WYLLIE, ANDREW, Dept. of Pathology, CRC Lab- VARMUS, HAROLD,Director's Office, National In- oratories, University of Edinburgh Medical stitutes of Health, Bethesda, Maryland School, Edinburgh, Scotland, United King- VOGELSTEIN, BERT, Dept. of Oncology, Johns dom Hopkins University Oncology Center, Balti- XIANG, JIALING, Dept. of Tumor Cell Biology, St. more, Maryland Jude Children's Research Hospital, Mem- VOGT, PETER, Dept. of Molecular and Experimen- phis, Tennessee tal Medicine, Scripps Research Institute, La XIONG, YUE, Dept. of Biochemistry and Bio- Jolla, California physics, University of North Carolina, WADGAONKAR, RAJ, Dept. of Oncology, Hoff- Chapel Hill mann-La Roche, Inc., Nutley, New Jersey Xu, GANGFENG, NDM Dept., Dana-Farber Can- WATSON, ROGER, St. Mary's Hospital Medical cer Institute, Boston, Massachusetts School, Ludwig Institute for Cancer Re- Xu, JUNZHE,Dept. of Internal Medicine, Universi- search, London, United Kingdom ty of Michigan, Ann Arbor WEBER, BARBARA,Dept. of Internal Medicine and YANG, YILI, Dept. of Immune Cell Biology, Na- Genetics, University of Michigan Medical tional Institutes of Health, Bethesda, Mary- Center, Ann Arbor land WEINBERG, ROBERT, Dept. of Biology, Whitehead YANG-YEN, HSIN-FANG, Institute of Molecular Institute for Biomedical Research, Cam- Biology, Academia Sinica, Nang-Kang, bridge, Massachusetts Taipei, Taiwan WEINMANN, ROBERTO,Bristol-Myers Squibb Phar- YEH, HEIDI, Lab. of Human Carcinogenesis, Na- maceutical Research Institute, Princeton, tional Cancer Institute, National Institutes of New Jersey Health, Bethesda, Maryland WESTPHAL, EVA-MARIA, Lab. of Molecular Car- YEN, JEFFREYJ.Y., Institute of Biomedical Ser- cinogenesis, NIH-National Institute of En- vices, Academia Sinica, Nang-Kang, Taipei, vironmental Health Sciences, Research Tri- Taiwan angle Park, North Carolina YIN, XIAO-MING, Howard Hughes Medical Insti- WHITE, EILEEN, Dept. of Biological Sciences, Cen- tute, Washington University Medical Center, ter for Advanced Biotechnology and Medi- St Louis, Missouri cine, Rutgers University, Piscataway, New YOSHIDA, MINORU, Dept. of Agricultural Chemis- Jersey try, University of Tokyo, Japan WIGLER, MICHAEL, Cold Spring Harbor Labora- You, MING, Dept. of Pathology, Medical College tory, Cold Spring Harbor, New York of Ohio, Toledo WILLEMS, LUC, Dept. of Molecular Biology, Sci- YOUNG, PAUL, Dept. of Biology, Queen's Uni- ences Agronomiques de Gembloux, Gem- versity, Kingston, Ontario, Canada bloux, Belgium ZHANG, HAILAN, Center for Advanced Biotech- WILLIAMS, BART, Dept. of Biology, Center for nology and Medicine, Piscataway, New Cancer Research, Massachusetts Institute of Jersey Technology, Cambridge, Massachusetts ZHANG, JIAO JIAO, Mt. Sinai School of Medicine, WILLIAMSON, KATHLEEN, MRC Human Genetics New York, New York Unit, Western General Hospital, Edinburgh, ZHANG, QIANG, Dept. of Pathology, University of Scotland, United Kingdom Chicago, Chicago, Illinois WIRNITZER, UTA, Pharmaforschungszentrum, In- ZILLIAN, OLAV, Institut ftir Molecularbiologie, stitut ftir Toxikologie IC, Wuppertal, Ger- Universit~it Ztirich, Switzerland many ZUR HAUSEN, HARALD, Deutsches Krebs- WISEMAN, ROGER, Lab. of Molecular Carcinogen- forschungszentrum, Heidelberg, Germany First row: E Neiman; H. Varmus; F. Collins, C. Rogler Second row: E Young, R. Schimke; R. Sager, E Vogt Third row: K. Culver; J. Sklar; B. Vogelstein; A. Kamb Fourth row: C. Greider, D. Ron; M.C. King; A. Nordheim First row: D. Stewart, F. McCormick; M. Oren; N. Short, T. Jacks Second row: G. Peters, J. Witkowski, M. Bishop, C. Greider; E. Harlow, C. Harris, D. Beach Third row: D. Galloway, N. Harter; T. Kelly, B. Stillman Fourth row: Picnic Foreword

Investigation of the mechanistic aspects of cancer has its roots in studies on tumor viruses and their effects on cell proliferation, function, and growth. This outstanding progress is well documented in previous Cold Spring Harbor Symposia on Quantitative Biology. The classic 1974 Symposium on Tumor Viruses, followed by the 1979 Symposium on Viral Oncogenes, chronicled the valuable insights that the study of viruses provided regarding the cancer problem. Studies on the genetics of human cancer arose from cytological observations of the abnormalities that are present in the chromosomes of tumor cells. Quite a number of the genes affected by either a translocation breakpoint, amplifica- tion, deletion, or point mutation had been identified by the time the Laboratory hosted a comprehen- sive meeting on the Origins of Human Cancer in our centennial year of 1990. In the early to mid 1980s, progress on the development of chromosome mapping strategies and the accumulation of DNA probes that identified polymorphisms, encouraged by the International Human Genome Project, enabled the identification of other genes that contributed to familial inheritance of high susceptibility to specific . This approach was very successful and led to a degree of optimism that one aspect of cancer, the multistep genetic process from early neoplasia to metastatic tumors, was beginning to be understood. It therefore seemed appropriate that the 59th Symposium on Quantitative Biology focus attention on the Molecular Genetics of Cancer. The concept was to combine the exciting progress on the identification of new genetic alterations in human tumor cells with studies on the function of the cancer gene products and how they go awry in tumor cells. Such an undertaking would have been most difficult without valuable advice from many colleagues. Principal among these were Ed Harlow, Eric Fearon, Bert Vogelstein, Thea Tlsty, and Michael Gottesman. I also thank David Stewart, Director of the meetings program at the Laboratory, who made this organizational task more efficient. The meeting was held from June 1 to June 8, 1994 and was attended by a record 421 participants, with 86 oral presentations in 14 sessions and 185 poster presentations on three separate afternoons. Outstanding first night introductory lectures by Leland Hartwell, Robert Weinberg, Bert Vogelstein, and Suzanne Cory set a high standard that was maintained throughout the next 7 days. Harold Varmus, whom we are fortunate to have as the current Director of the National Institutes of Health, presented a masterful Dorcas Cummings Lecture to members of our local community. I am grateful to Ed Harlow who generously agreed to summarize the meeting. He provided the audience with sound advice, good humor, and great insight. Essential funds that supported this meeting were obtained from the National Cancer Institute (a division of the National Institutes of Health) and the U.S. Department of Energy, Office of Health and Environmental Research. Additional support came from our ever more important and needed Corporate Sponsors: Alafi Capital Company; American Cyanamid Company; Amgen Inc.; Becton Dickinson and Company; Biogen; Bristol-Myers Squibb Company; Chugai Pharmaceutical Co., Ltd.; Ciba-Geigy Corporation; Diagnostic Products Corporation; The Du Pont Merck Pharmaceutical Company; Forest Laboratories, Inc.; Genentech, Inc.; Glaxo; Hoffmann-La Roche Inc.; Johnson & Johnson; Kyowa Hakko Kogyo Co., Ltd.; Life Technologies, Inc.; Mitsubishi Kasei Institute of Life Sciences; Monsanto Company; New England BioLabs, Inc.; Oncogene Science, Inc.; Pall Corporation; The Perkin-Elmer Corporation; Pfizer Inc.; Research Genetics; Sandoz Research Institute; Schering- Plough Corporation; SmithKline Beecham Pharmaceuticals; Sterling Winthrop Inc.; Sumitomo Phar- maceuticals Co., Ltd.; Takeda Chemical Industries, Ltd.; Toyobo Co., Ltd.; Wyeth-Ayerst Research; and Zeneca Group PLC. Once again, I thank the efficient staff in our meetings office, now under the direction of David Stewart, particularly Diane Tighe, Mikki McBride, and Andrea Stephenson for handling all the administrative aspects. Herb Parsons and his staff provided excellent audiovisual assistance. The organization of this meeting greatly relied on the marvelous work of my assistant Delia Costello who made this time-consuming task a pleasure. Finally, it was again a pleasure to work with the efficient Publications Office, under the direction of John Inglis, particularly Nancy Ford, Patricia Barker, and Joan Ebert. Their efficiency made this volume possible.

Bruce Stillman January 17, 1995

xix Contents

Symposium Participants v Foreword xix

Control of Cell Cycle and Cell Growth

The Cancer Cell and the Cell Cycle Clock M. Hatakeyama, R.A. Herrera, T. Makela, S.F. Dowdy, T. Jacks, and R.A. Weinberg D-Type Cyclins and Their Cyclin-dependent Kinases: G l Phase Integrators of the Mitogenic Response C.J. Sherr, J. Kato, D.E. Quelle, M. Matsuoka, and M.F. Roussel 11 p21 Is a Component of Active Cell Cycle Kinases H. Zhang, G.J. Hannon, D. Casso, and D. Beach 21 Cyclins, Cdks, and Cyclin Kinase Inhibitors J.M. Roberts, A. Koff, K. Polyak, E. Firpo, S. Collins, M. Ohtsubo, and J. Massagu~ 31 Role of a Cell Cycle Regulator in Hereditary and Sporadic Cancer A. Kamb 39 p16 INK4 Mutations and Altered Expression in Human Tumors and Cell Lines A. Okamoto, D.J. Demetrick, E.A. Spillare, K. Hagiwara, S.P. Hussain, W.P. Bennett, K. Forrester, B. Gerwin, M.S. Greenblatt, M. Serrano, M. Shiseki, J. Yokota, D.H. Beach, and C.C. Harris 49 Molecular Genetic Approaches to the Study of Cellular Senescence T.J. Goletz, J.R. Smith, and O.M. Pereira-Smith 59 Molecular and Cell Biology of Replicative Senescence G.P. Dimri and J. Campisi 67 Growth Suppression by Members of the Retinoblastoma Protein Family L. Zhu, G.H. Enders, C.-L. Wu, M.A. Starz, K.H. Moberg, J.A. Lees, N. Dyson, and E. Harlow 75 The Adenovirus EIA-associated 300-kD Protein Exhibits Properties of a Transcription- al Coactivator and Belongs to an Evolutionarily Conserved Family R. Eckner, Z. Arany, M. Ewen, W. Sellers, and D.M. Livingston 85 The Corral Hypothesis: A Novel Regulatory Mode for Retinoblastoma Protein Function W.-H. Lee, Y. Xu, F. Hong, T. Durfee, M.A. Mancini, Y.-C. Ueng, P.-L. Chen, and D. Riley 97 The Max Transcription Factor Network: Involvement of Mad in Differentiation and an Approach to Identification of Target Genes P.J. Hurlin, D.E. Ayer, C. Grandori, and R.N. Eisenman 109 BCL-6 and the Molecular Pathogenesis of B-Cell Lymphoma R. Dalla-Favera, B.H. Ye, F. Lo Coco, C.-C. Chang, K. Cechova, J. Zhang, A. Migliazza, W. Mellado, H. Niu, S. Chaganti, W. Chen, P.H. Rao, N.Z. Parsa, D.C. Louie, K. Offit, and R.S.K. Chaganti 117 Functional Analysis of the TAN-1 Gene, a Human Homolog of Drosophila Notch J. Aster, W. Pear, R. Hasserjian, 11. Erba, F. Davi, B. Luo, M. Scott, D. Baltimore, and J. Sklar 125 Novel Oncogenic Mutations in the WT1 Wilms' Tumor Suppressor Gene: A t(11;22) Fuses the Ewing's Sarcoma Gene, EWS1, to WT1 in Desmoplastic Small Round Cell Tumor F.J. Rauscher Ili, L.E. Benjamin, W.J. Fredericks, and J.F. Morris 137 Ras Signal Transduction Pathway in Drosophila Eye Development H.C. Chang, F.D. Karim, E.M. O'Neill, I. Rebay, N.M. Solomon, M. Therrien, D.A. Wassarman, T. Wolff, and G.M. Rubin 147 Molecular Genetics of Proto-oncogenes and Candidate Tumor Suppressors in Caen- orhabditis elegans P.W.Sternberg, C.H. Yoon, J. Lee, G.D. Jongeward, P.S. Kayne, W.S. Katz, G. Lesa, J. Liu, A. Golden, L.S. Huang, and H.M. Chamberlin 155

xxi xxii CONTENTS

Proto-oncogenes and Plasticity in Cell Signaling J.M. Bishop, A.J. Capobianco, H.J. Doyle, R.E. Finney, M. McMahon, S.M. Robbins, M.L. Samuels, and M. Vetter 165 Activation of Ras and Other Signaling Pathways by Receptor Tyrosine Kinases J. Schlessinger and D. Bar-Sagi 173 Ras Partners L. Van Aelst, M.A. White, and M.H. Wigler 181 Proteins of the 14-3-3 Family Associate with Raf and Contribute to Its Activation E. Freed, F. McCormick, and R. Ruggieri 187 Regulation of the Cryptic Sequence-specific DNA-binding Function of p53 by Protein Kinases T.R. Hupp and D.P. Lane 195 DNA-binding Properties of the p53 Tumor Suppressor Protein C. Prives, J. Bar- gonetti, G. Farmer, E. Ferrari, P.. Friedlander, Y. Wang, L. Jayaraman, N. Pav- letich, and U. Hubscher 207 Functions of the p53 Protein in Growth Regulation and Tumor Suppression J. Lin, X. Wu, J. Chen, A. Chang, and A.J. Levine 215 Targets for Transcriptional Activation by Wild-type p53: Endogenous Retroviral LTR, Immunoglobulin-like Promoter, and an Internal Promoter of the mdm2 Gene Y. Barak, A. Lupo, A. Zauberman, T. Juven, R. Aloni-Grinstein, E. Gottlieb, V. Rotter, and M. Oren 225 E6-AP Directs the HPV E6-dependent Inactivation of p53 and Is Representative of a Family of Structurally and Functionally Related Proteins J.M. Huibregtse, M. Scheffner, and P.M. Howley 237 p53-Dependent Apoptosis In Vivo: Impact of p53 Inactivation on Tumorigenesis H. Symonds, L. Krall, L. Remington, M. Sdenz-Robles, T. Jacks, and T. Van Dyke 247

Checkpoints and Genome Stability

Cell Cycle Checkpoints, Genomic Integrity, and Cancer L. Hartwell, T. Weinert, L. Kadyk, and B. Garvik 259 Genomic Integrity and the Genetics of Cancer T.D. Tlsty, A. White, E. Livanos, M. Sage, H. Roelofs, A. Briot, and B. Poulose 265 DNA Damage Responses: p53 Induction, Cell Cycle Perturbations, and Apoptosis C.E. Canman, C.-Y. Chen, M.-H. Lee, and M.B. Kastan 277 Lymphocyte-specific Genetic Instability and Cancer I.R. Kirsch, J.M. Abdallah, V.L. Bertness, M. Hale, S. Lipkowitz, F. Lista, and D.P. Lombardi 287 Cell Cycle Checkpoint Control Is Bypassed by Human Papillomavirus Oncogenes D.A. Galloway, G.W. Demers, S.A. Foster, C.L. Halbert, and K. Russell 297 Telomerase, Cell Immortality, and Cancer C.B. Harley, N.W. Kim, K.R. Prowse, S.L. Weinrich, K.S. Hirsch, M.D. West, S. Bacchetti, H.W. Hirte, C.M. Counter, C.W. Greider, M.A. Piatyszek, W.E. Wright, and J.W. Shay 307 Three Unusual Repair Deficiencies Associated with Transcription Factor BTF2(TFIIH): Evidence for the Existence of a Transcription Syndrome W. Vermeulen, A.J. van Vuuren, M. Chipoulet, L. Schaeffer, E. Appeldoorn, G. Weeda, N.G.J. Jaspers, A. Priestley, C.F. Arlett, A.R. Lehmann, M. Stefanini, M. Mezzina, A. Sarasin, D. Bootsma, J.-M. Egly, and J.H.J. Hoeijmakers 317 Human Mismatch Repair Genes and Their Association with Hereditary Non-Polyposis Colon Cancer R.D. Kolodner, N.R. Hall, J. Lipford, M.F. Kane, M.R.S. Rao, P. Morrison, L. Wirth, P.J. Finan, J. Burn, P. Chapman, C. Earabino, E. Merchant, D.T. Bishop, J. Garber, C.E. Bronner, S.M. Baker, G. Warren, L.G. Smith, A. Lindblom, P. Tannergard, R.J. Bollag, A.R. Godwin, D.C. Ward, M. Nordenskjold, R.M. Liskay, N. Copeland, N. Jenkins, M.K. Lescoe, A. Ewel, S. Lee, J. Griffith, and R. Fishel 331 Defects in Replication Fidelity of Simple Repeated Sequences Reveal a New Mutator Mechanism for Oncogenesis M. Perucho, M.A. Peinado, Y. Ionov, S. Casares, S. Malkhosyan, and E. Stanbridge 339 CONTENTS xxiii

Ovarian Tumors Display Persistent Microsatellite Instability Caused by Mutation in the Mismatch Repair Gene hMSH-2 K. Orth, J. Hung, A. Gazdar, M. Mathis, A. Bowcock, and J. Sambrook 349 Loss of Imprinting in Human Cancer A.P. Feinberg, L.M. Kalikin, L.A. Johnson, and J.S. Thompson 357 Enhanced Cell Survival and Tumorigenesis S. Cory, A. Strasser, T. Jacks, L.M. Corcoran, 7". Metz, A.W Harris, and J.M. Adams 365

Apoptosis

The Genetics of Programmed Cell Death in the Nematode Caenorhabditis elegans H.R. Horvitz, S. Shaham, and M.O. Hengartner 377 Bcl-2 Gene Family and the Regulation of Programmed Cell Death X.-M. Yin, Z.N. Ohvai, D.J. Veis-Novack, G.P. Linette, and S.J. Korsmeyer 387 Control of p53-dependent Apoptosis by EIB, Bcl-2, and Ha-ras Proteins E. White, S.-K. Chiou, L. Rao, P. Sabbatini, and H.-J. Lin 395 Apoptosis in Carcinogenesis: The Role of p53 A.H. Wyllie, P.J. Carder, A.R. Clarke, K.J. Cripps, S. Gledhill, M.F. Greaves, S. Griffiths, D.J. Harrison, M.L. Hooper, R.G. Morris, C.A. Purdie, and C.C. Bird 403 Cellular Senescence and Cancer J.C. Barrett, L.A. Annab, D. Alcorta, G. Preston, P. Vojta, and Y. Fin 411 Apoptosis and the Prognostic Significance of p53 Mutation S.W. Lowe, S. Bodis, N. Bardeesy, A. McClatchey, L. Remington, H.E. Ruley, D.E. Fisher, T. Jacks, J. Pelletier, and D.E. Housman 419

Genetic Models

Transgenic Approaches to the Analysis of ras and p53 Function in Multistage Carcinogenesis C.J. Kemp, P.A. Burns, K. Brown, H. Nagase, and A. Balmain 427 Mouse Model Systems to Study Multistep Tumorigenesis A. Berns, N. van der Lugt, M. Alkema, M. van Lohuizen, J. Domen, D. Acton, J. Allen, P.W. Laird, and J. Jonkers 435 Tumorigenic and Developmental Effects of Combined Germ-line Mutations in Rb and p53 B.O. Williams, S.D. Morgenbesser, R.A. DePinho, and T. Jacks 449 Insulin-like Growth Factor II Is Focally Up-regulated and Functionally Involved as a Second Signal for Oncogene-induced Tumorigenesis P. Naik, G. Christofori, and D. Hanahan 459 Angiostatin: A Circulating Endothelial Cell Inhibitor That Suppresses Angiogenesis and Tumor Growth M.S. O'Reilly, L. Holmgren, Y. Shing, C. Chen, R.A. Rosenthal, Y. Cao, M. Moses, WS. Lane, E.H. Sage, and J. Folkman 471 The p53 Tumor Suppressor Gene Inhibits Angiogenesis by Stimulating the Production of Thrombospondin K.M. Dameron, O.V. Volpert, M.A. Tainsky, and N. Bouck 483 Defining the Steps in a Multistep Mouse Model for Mammary Carcinogenesis H.E. Varmus, L.A. Godley, S. Roy, I.C.A. Taylor, L. Yuschenkoff, Y.-P Shi, D. Pinkel, J. Gray, R. Pyle, C.M. AIdaz, A. Bradley, D. Medina, and L.A. Donehower 491 The Adenomatous Polyposis Coli Gene of the Mouse in Development and Neoplasia W.F. Dove, C. Luongo, C.S. Connelly, K.A. Gould, A.R. Shoemaker, A.R. Moser, and R.L. Gardner 501 Genetic Instability and Apoptotic Cell Death during Neoplastic Progression of v-myc- initiated B-cell Lymphomas in the Bursa of Fabricius P.E. Neiman, J. Summers, S.J. Thomas, S. Xuereb, and G. Loring 509 Colorectal Cancer and the Intersection between Basic and Clinical Research B. Vogelstein and K.W. Kinzler 517 ~iv CONTENTS

Human Cancer Genes and Their Products

Green Pigs, Red Herrings, and a Golden Hoe: A Retrospective on the Identification of BRCA1 and the Beginning of Its Characterization E.A. Ostermeyer, L.S. Friedman, E.D. Lynch, C.L Szabo, P. Dowd, M.K. Lee, S.E. Rowell, and M.-C. King 523 Progress toward Isolation of a Breast Cancer Susceptibility Gene, BRCA1 B.L. Weber, K.J. Abel, F.J. Couch, S.D. Merajver, S.C. Chandrasekharappa, L. Castilla, D. McKinley, P.P. Ho, K. Calzone, T.S. Frank, J. Xu, L.C. Brody, and F.S. Collins 531 RNA Genetics of Breast Cancer: Maspin as Paradigm R. Sager, S. Sheng, A. Anisowicz, G. Sotiropoulou, Z. Zou, G. Stenman, K. Swisshelm, Z. Chen, M.J.C. Hendrix, P. Pemberton, K. Rafidi, and K. Ryan 537 Acute Myeloid Leukemia with Inv(16) Produces a Chimeric Transcription Factor with a Myosin Heavy Chain Tail P. Liu, N. Seidel, D. Bodine, N. Speck, S. Tarlk, and F.S. Collins 547 Genetic Alterations in the Chromosome 22q12 Region Associated with Development of Neuroectodermal Tumors G. Thomas, O. Delattre, J. Zucman, P. Merel, C. Desmaze, T. Melot, M. Sanson, K. Hoang-Xuan, B. Plougastel, P. Dejong, G. Rouleau, and A. Aurias 555 Molecular Genetic Changes Found in Human Lung Cancer and Its Precursor Lesions A.F. Gazdar, S. Bader, J. Hung, Y. Kishimoto, Y. Sekido, K. Sugio, A. Virmani, J. Fleming, D.P. Carbone, and J.D. Minna 565 Molecular Characterization of QM, a Novel Gene with Properties Consistent with Tumor Suppressor Function E. Stanbridge, A. Farmer, A. Mills, T. Loftus, D. Kongkasuriyachai, S. Dowdy, and B. Weissman 573 Barrett's Esophagus: A Model of Human Neoplastic Progression K. Neshat, C.A. Sanchez, P.C. Galipeau, D.S. Cowan, S. Ramel, D.S. Levine, and B.J. Reid 577 Detection of Genetic Loss in Tumors by Representational Difference Analysis N.A. Lisitsyn, F.S. Leach, B. Vogelstein, and M.H. Wigler 585 Genetic Approaches to Defining Signaling by the CML-associated Tyrosine Kinase BCR-ABL D.E.H. Afar, A. Goga, L. Cohen, C.L. Sawyers, J. McLaughlin, R.N. Mohr, and O.N. Witte 589 The AML1 Gene in the 8;21 and 3;21 Translocations in Chronic and Acute Myeloid Leukemia G. Nucifora and J.D. Rowley 595 Expression of P-Glycoprotein in Normal and Malignant Rat Liver Cells C.H. Lee, G. Bradley, and V. Ling 607 Genes Coding for Tumor-specific Rejection Antigens T. Boon, B. Van den Eynde, H. Hirsch, C. Moroni, E. De Plaen, P. van der Bruggen, C. De Smet, C. Lurquin, J.-P. Szikora, and O. De Backer 617 Pathogenesis of Cancer of the Cervix H. zur Hausen and F. ROsl 623 Autocrine Mechanism for met Proto-oncogene Tumorigenicity S. Rong and G.F. Vande Woude 629 Studies of the Deleted in Colorectal Cancer Gene in Normal and Neoplastic Tissues E.R. Fearon, B.C. Ekstrand, G. Hu, W.E. Pierceall, M.A. Reale, and S.H. Bigner 637 Molecular Cytogenetics of Human Breast Cancer J.W. Gray, C. Collins, I.C. Hender- son, J. Isola, A. Kallioniemi, O.-P. Kallioniemi, H. Nakamura, D. Pinkel, T. Stokke, M. Tanner, and F. Waldman 645 Genetic Alterations in Prostate Cancer W.B. Isaacs, G.S. Bova, R.A. Morton, M.J.G. Bussemakers, J.D. Brooks, and C.M. Ewing 653 Multicellular Resistance: A New Paradigm to Explain Aspects of Acquired Drug Resistance of Solid Tumors R.S. Kerbel, J. Rak, H. Kobayashi, M.S. Man, B. St. Croix, and C.H. Graham 661 CONTENTS xxv

Genetic Methods for Diagnosis and Cancer Therapy

Overcoming Complexities in Genetic Screening for Cancer Susceptibility S.H. Friend, R. Iggo, C. Ishioka, M. Fitzgerald, I. Hoover, E. O'Neill, and T. Frebourg 673 Exploiting Multidrug Resistance to Treat Cancer M.M. Gottesman, S.V. Ambudkar, B. Ni, J.M. Aran, Y. Sugimoto, C.O. Cardarelli, and L Pastan 677 Toxicity and Immunologic Effects of In Vivo Retrovirus-mediated Gene Transfer of the Herpes Simplex-Thymidine Kinase Gene into Solid Tumors K.W. Culver, D.W Moorman, R.R. Muldoon, R.M. Paulsen, Jr., J.L. Lamsam, H.W. Walling, and C.J. Link, Jr. 685 Gene Transfer and Bone Marrow Transplantation M.K. Brenner, H.E. Heslop, D. Rill, C. Li, T. Nilson, M. Roberts, C. Smith, R. Krance, and C. Rooney 691 Molecular Genetic Interventions for Cancer G.J. Nabel, E.G. Nabel, Z. Yang, B.A. Fox, G.E. Plautz, X. Gao, L. Huang, S. Shu, D. Gordon, and A.E. Chang 699 An Introduction to the Puzzle E. Harlow 7O9

Author Index 725

Subject Index 729