STEROID RECEPTORS IN HEALTH AND DISEASE SERONO SYMPOSIA, USA Series Editor: James Posillico

ACROMEGALY: A Century of Scientific and Clinical Progress Edited by Richard J. Robbins and Shlomo Melmed

BASIC AND CLINICAL ASPECTS OF GROWTH HORMONE Edited by Barry B. Bercu

THE PRIMATE OVARY Edited by Richard L. Stouffer

SOMATOSTATIN: Basic and Clinical Status Edited by Seymour Reichlin

STEROID RECEPTORS IN HEALTH AND DISEASE Edited by Virinder K. Moudgil

A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further infor• mation please contact the publisher. STEROID RECEPTORS IN HEALTH AND DISEASE

Edited by Virinder K. Moudgil Oakland University Rochester, Michigan

PLENUM PRESS • NEW YORK AND LONDON library of Congress Cataloging in Publication Data Meadow Brook Conference on Steroid Receptors in Health and Disease (tst(tst:: t987 : Rochester, Mich .) Ste roid receptors in health and disease / edited by Virinder K. Moudgil. p. cm . "Proc" Proceedingseedings of the Meadow Brook Conference on Steroid Receptors in Health and Disease, spon• sored by Serono Symposia. USA and Oakland University. held September 20-23, 19871987.. in Rochester. Michigan ··-T.p. verso. Includes bibliographies and indexes. IS8N 978-1-4684-5543-4 IS8N 978-1-4684-5541-0 (eBook) 00110.1007/978-1-4684-5541-0 I . Steroid hormones-Receptors-Congresses. 1. Moudgil, V. V. K. K. (Virinder K.), 1945- . 11. Sereno Symposia, USA. III.Ill. Oakland Universityly. IV. Title. [oNlM[oNlM:: tt. . Receptors , Sleroid-congresses. W3 ME3781st 1987s / WK 150 M482 1987sJ1987sj oP571.7.M42 1987 512 '. 405-dcI9 oNlM/olCoNlM/olC 88·22477 for library of Congress CIP

The views expressed in this volume are the res ponsibilityponsibility of the named authors. Great care has been taken to maintain the accuracy of the information contained in the volume. However , ne it her Plenum Press. Serono Symposia. USA. nor the editors can be held responsible tfoorr errors or any consequen ces arising fromtrem the use ofot information contained herein. Some of the names of products referred to In th is book may be registered trademarks or propriet<.ry names. although specific references to this fact may not be made; hohowever,wever, the use of a name without designalions is not to be const rued as a representation by the publisher or editors that it is in the pub lic domain.domain. In additionaddition.. the mention of specific companies or of their products or proprietary names does not imply any endorsement or recommendation on the part of the publisher or editors .

Proceedings of the Meadow Brook Conference on Steroid Receptors in Health and ~sease ,, sponsored by Serono SymposiaSymposia , USA and Oakland Un iversity . held September 20-23. 1987. in Rochester, Michigan

© 1988 PlenumPlen um Press.Press . New York SoItcover rep rinJ 01 the hardcovedcoverr 1St eO'tiooeOtian 1988 A Div iSion 01 Plenum Publishing Corporation 233 Spring Street . New York, N.Y. 10013 All rights resef\led No part of this book may be reproduced, stored in a retrieval system. or transmined in any form or by any means , electronic , mechanical, photocopying. microfilming. recording.recording . or otherwise. without written permission from the PublishePublisherr SCIENTIFIC COMMITTEE

Virinder Moudgil, Chairman Rochester, MI

Etienne-Emile Baulieu Paris, France

Jack Gorski Madison, WI

Benita Katzenellenbogen Urbana, IL

David Toft Rochester, MN

James Wittliff Louisville, KY

ORGANIZING SECRETARY

Dr. James T. Posillico Serono Symposia, USA Randolph, Massachusetts

v PREFACE

During the last two decades, progress in steroid hormone research has resulted in the development of new approaches to contraception as well as diagnosis and treatment of endocrine disorders and . Although significant advances have been made in the purification, characterization, immunochemistry and molecular biology of steroid receptors, the precise molecular mechanism of steroid hormone action has remained obscure. This book captures the detailed presentations made at the first conference on Steroid Receptors in Health and Disease held at Meadow Brook Hall, Oakland University in the fall of 1987. The purpose of this international con• ference was to facilitate scientific exchange toward a better understand• ing of the mode of action of steroid hormones. The scientific sessions consisted of poster presentations and state-of-the-art lectures, the latter of which make up this volume. The first chapter is meant to provide the reader with a more general background of the topics covered in the book, as well as to discuss certain theme-related issues that are either not yet well-established or accepted or are in the stage of infancy. It is hoped that this volume will serve as a useful treatise for students and investigators interested in basic and clinical aspects of biological regulation by steroid hormones.

A task of this magnitude could not have been undertaken without the encouragement, advice and continued generous assistance of the members of the scientific committee. I am gratefully indebted to Drs. Etienne Baulieu, Jack Gorski, Benita Katzenellenbogen, David Toft, and James Wittliff for providing guidance and direction in the planning and execu• tion of the scientific program. The stimulating and relaxed ambiance was provided by the venue of the conference, Meadow Brook Hall, a national treasure and designated historic site in the State of Michigan. Thanks are due to Drs. Joanne Williams, Theodore Landau, and Naomi Eliezer, Mr. John Shiff, Mr. Cliff Hurd, Ms. Rita Perris, and many of our students and colleagues whose invaluable help in the planning and operation of the conference made it a successful and memorable event.

The conference was made possible through generous financial support from Serono Symposia, USA, Oakland University and Meadow Brook Hall. Local arrangements were facilitated by thoughtful contributions from William Beaumont Hospital, Schering Corporation, The Squibb Institute for Medical Research, Oxford Biomedical Research and Protein International. The excellent cooperation from the authors and the timely and skillful assistance from the publications and editorial staff of Serono Symposia, USA and Plenum Press has made the job of editing this volume an enjoyable experience. I am particularly indebted to Dr. James Posillico and his staff for the support and encouragement received from the time of planning the conference to the compilation of this volume.

Virinder K. Moudgil

vii CONTENTS

I. INTRODUCTION AND KEYNOTE ADDRESS

1. Steroid Receptors in Health and Disease • • • • • • 3 Virinder K. Moudgil

2. Steroid Receptors: A Historical Perspective 25 Jack Gorski

II. RECEPTOR STRUCTURE AND MOLECULAR ORGANIZATION

3. Intracellular Localization of Steroid Hormone Receptors: Immunocytochemical Analysis • • • • • • 35 Jean-Marie Gasc and Etienne-Emile Baulieu

4. Immunocytochemistry of Estrogen and Progestin Receptors in the Primate Reproductive Tract • • • • • • • • 47 Robert M. Brenner, Maryanne C. McClellan, Neal B. West

5. Structure, Functional Domains and Subcellular Distribution of Glucocorticoid Receptor • • • • • • • • • • . • • 71 Jan Carlstedt-Duke, Ann-Charlotte Wikstrom, and Jan-Ake Gustafsson

6. Hormone-Dependent Phosphorylation of the Avian Progesterone Receptor • • . • • • • • 85 William P. Sullivan, David F. Smith, and David O. Toft

III. RECEPTOR MODIFICATIONS AND HORMONE REGULATION

7. Hormone-Dependent and Hormone-Independent Conformational Transitions of the • . . • • • • 99 Jeffrey C. Hansen and Jack Gorski

8. Human Progesterone Receptors A and B: Two Independent, Functional Forms •••..•• III Kathryn B. Horwitz

9. Androgen Regulation of : Studies of Ornithine Decarboxylase in Murine Kidney 119 Olli A. Janne, Noreen J. Hickok, Mervi Julkunen, Anne Crozat, Leonard Eisenberg, and Evie Melanitou 10. Advances in Uterus Estradiol Receptor Phosphorylation on Tyrosine and Preliminary Evidences that Liver Glucocor- ticoid Receptor Might Be Phosphorylated on Tyrosine 133 G. Castoria, A. Migliaccio, M. Di Domenico, M. Pagano, A. Rotondi, E. Nola, and F. Auricchio

IV. RECEPTOR GENE STRUCTURE AND FUNCTION

11. Functional Analysis of the Estrogen and Progesterone Receptors . • • . . • • • • • . • . . . • . . • . . .. 151 H. Gronemeyer, M. Berry, M. T. Bocquel, J. Eul, S. Green, J. M. Jeltsch, A. Krust, V. Kumar, M. E. Meyer, G. Stack, C. Stricker, B. Turcotte, and P. Chambon

12. Molecular Determinants of Positive and Negative Regulation by Ligand-Regulated Transcription Factors . . . • • • 163 Michael G. Rosenfeld, Christopher K. Glass, Rodrigo Franco, Stuart Adler, Marian L. Waterman, and Xi He

13. The Mammalian Progesterone Receptor: Cloning, Immuno- localization and Mechanism of Interaction with DNA 177 Jean-Francois Savouret, Hugues Loosfelt, Micheline Misrahi, Michel Atger, Alain Bailly, Martine Perrot-Applanat, Anne Guiochon-Mantel, Michel Rauch, and Edwin Milgrom

14. Isolation and Sequence of the Human Glucocorticoid Receptor Gene Promoter. Cloning of the Human Androgen Receptor cDNA ...... 187 Manjapra V. Govindan, Marco Burelle, Celine Cantin, Martine Devic, Claude Labrie, Fernand Labrie, Yves Lachance, Gilles Leblanc, Claude Lefebvre, Pravin Patel, Jacques Simard, and Udo Stropp

V. BIOCHEMICAL ACTIONS AND ANTIHORMONES

15. Estrogen and Antiestrogen Regulation of Proliferation and Protein Synthesis of Human Breast Cells 209 Benita S. Katzenellenbogen, Yhun Yhong Sheen, Catherine E. Snider, and Yolande Berthois

16. An Estrogen Induced Protease in : From Basic Research to Clinical Applications . 221 Henri Rochefort, Patrick Augereau, Pierre Briozzo, Francoise Capony, Vincent Cavailles, Marcel Garcia, Muriel Morisset, Gilles Freiss, and Francoise Vignon

17. Nuclear Acceptor Sites: Interaction with Estrogen• Versus Antiestrogen-Receptor Complexes 233 Thomas S. Ruh, Mary F. Ruh, and Raj K. Singh

18. Antisteroid Hormones, Receptor Structure and Heat-Shock Protein MW 90,000 (hsp 90) ...... 251 Etienne-Emile Baulieu

VI. PHARMACOLOGICAL AND CLINICAL CORRELATIONS

19. Neural Estrogen and Progestin Receptors and the Neurochemistry of Reproductive Behavior and Sexual Differentiation . .. 265 Bruce S. McEwen

x 20. Estrogen Actions on Endometrial Adenocarcinoma 271 Erlio Gurpide, Christian F. Holinka, Yuzuru Anzai, Hiroki Hata, Hiroyuki Kuramoto, Sharon Kassan, and Leszek Markiewicz

21. Structural Features and Clinical Significance of Estrogen Receptors •••.••••• 287 James L. Wittliff, Joseph C. Allegra, Thomas G. Day, Jr., and Salman M. Hyder

22. The Role of the Ras Oncogene in Human Mammary Cancer 313 Edward P. Gelmann, Connie Agnor, and Marc E. Lippman

Author Index • 325

Subject Index 327