Molecular Mechanism Of Steroid Hormone Action

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 cancers. 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.

Steroid Hormone Action is a comprehensive overview of the molecular mechanisms by which these hormones regulate the expression of specific target genes. The book covers the structure of steroid receptors, transcriptional activation and repression, and also contains chapters on steroid bindingproteins and steroidogenesis. Steroid receptors represent one of the best characterized transcription factors so that the book will be of general interest to Molecular Biologists studying eucaryotic gene regulation. Chapters on the mechanisms of action of steoid antagonists and defective receptorsin target cells will be of particular interest to Endocrinologists and Clinicians. In such a rapidly progressing field it is difficult to keep up with all the literature but this book, written by international experts, focuses on the most important advances that have been made recently.

Within the last two decades endocrinological research has taken a definite tum toward biochemistry and molecular biology. This has resulted in a new discipline called' 'molecular endocrinology. " Studies on the mechanism of hormone action have continued to make headlines with fundamental discov eries in receptor action and gene regulation. Recently the insect endocrino logists have also begun to explore the molecular mechanism of steroid hor mone action taking advantage of the vast number of Drosophila mutants, the library of Drosophila gene, and several well-characterized cell-lines. The availability ofthe recombinant DNA technology has provided a truly revolu tionary tool in the hands of the molecular endocrinologists. "Gene Regula tion by Steroid Hormones" is compiled and presented in this frontier spirit, and we hope that this volume will serve not only the active investigators in the field but will also be very useful to students and researchers with a gen eral interest in regulatory biology. The book is an offshoot of the Conference on Molecular Mechanism of Steroid Hormone Action held at the Meadow Brook Mansion of Oakland University in the fall of 1978. We wish to acknowledge the financial assist ance from the National Science Foundation and Oakland University. The conferees will never forget the warmest hospitality of Dr. LOWELL EKLUND and his staff at the Meadow Brook center and we also wish to express per sonal gratitude to many of our students and colleagues for helping us to make the conference a great success.

The purpose of this book is to focus attention on recent developments in steroid and sterol hormone action. Many authors have generously contributed to the book. As a result, there is a great diversity of opinion! A majority of the chapters deal with steroid or sterol hormone receptors. This is not meant to imply that receptor-mediated mechanisms are the sole or even the most important mechanisms by which steroid hormones act in the cell. There is wealth of evidence showing that other, non-receptor events, are important also. Steroid hormone recep tor research and the study of nuclear events mediated by steroids are presently the most intensely studied aspects of sterol hormone action and our selection of topics reflects this trend. We have also included chapters on vitamin 0 sterols and thyroid hormone in the book, as there is pood evidence that these hormones act in a manner similar to other classical steroids. 1 IMMUNOCHARACTERIZATION OF THE NUCLEAR ACCEPTOR SITES FOR THE AVIAN OVIDUCT PROGESTERONE RECEPTOR A. GOLDBERGER, M. HORTON, T. C. SPELSBERG Department of Biochemistry and Molecular Biology, Mayo Clinic and Mayo Graduate School of Medicine, Rochester, MN 55905 INTRODUCTION It is well known that steroid hormones, certain vitamins and sterols, enter target cells and bind to specific protein receptors in the cyto plasm or nucleus (1-4). This binding is saturable, high affinity, and steroid specific.

Receptors and Gene Expression It is now more than three years since the last Meadow Brook Conference on Hormones, and a great deal has happened in the meantime. We have become comfortable with the totally unanticipated fact that the coding sequences of genes are in discontinuous arrangements and that the RNA transcribed from them must be extensively processed to form messenger RNA. We have also learned about the strategy of "mixing and matching" of genetic segments so that a small amount of DNA can go a long way in producing a huge variety of different proteins, as in the immunoglobulin system. The explosive effort directed toward DNA sequence analysis has led us to the conclusion that there are signals within the DNA that specify sites of transcription initiation and possibly sites for interacting with regulatory molecules such as hor mones and their receptors. The current intense interest in the structure of chromatin beyond the nucleosome-that is, the superstructural characteris tics of the genetic material-is finally yielding meaningful results that give promise for understanding the regulation of gene activity. ROBERT F. GOLDBERGER Preface Research on the molecular mechanism of steroid hormone action continues at an extraordinary pace and a great deal of progress has been made. Steroid hormones have been localized on target genes providing the long awaited evidence for the concept of a direct effect of the steroid-receptor complex on gene regulation. Purified steroid receptors have been dissected to identify different functional domains.

Steroids are essential hormones that regulate biological processes across their lifespan. Steroid hormone production and action must be tightly controlled otherwise there can be detrimental effects on physiological function leading to disease. This reprint contains original and review articles by experts at the cutting edge of their fields published in a Special Issue on the "Molecular mechanisms of steroid hormone biosynthesis and action" of the International Journal of Molecular Sciences. The topics include: 1) Steroid hormone biosynthesis, including substrate availability, mechanism of steroidogenic enzyme action, and the impact of mutations; 2) Molecular and cellular regulation of steroidogenesis, including steroidogenic cell response to hormone stimulation, signaling pathways, kinases, transcription factors, and gene expression; 3) Molecular mechanisms of endocrine disruptor action on steroidogenic cells; and 4) New tools and approaches to detect and study steroid hormones.

This volume is an outgrowth of a symposium held at the University of Michigan, Ann Arbor, Michigan, October 27-29, 1975. This symposium was organized to bring together basic scientists and clinicians for the purpose of exchanging new ideas and the latest information in the area of Steroid Hormone Action and Cancer. The design of the symposium included both formal plenary sessions and informal roundtable discussion groups, the chapters of this volume being drawn primarily from these proceedings. During the last quarter of a century considerable progress has been made toward understanding the molecular mechanisms in volved in steroid hormone action. It now appears that the mechan sim of action of the four major classes of steroid hormones is qualitatively similar. Research during the past decade has demonstrated steroid hormone receptors in a variety of normal and neoplastic tissues. Receptor-containing neoplasms have been shown to be hormone-dependent and undergo regression when treated with hormone antagonists. Natural and synthetic steroids also have been employed for many years to successfully treat various types of cancer, for example: estrogens, androgens and progestagens for breast cancer; estrogens and progestagens for prostatic carcinoma; progestagens for endometrial carcinoma; and corticoids for leu kemias. All of these neoplasms have now been found to possess receptors for the steroids empirically used in their treatment.