The Second International CBT (Center for Biotechnology) Synposium was held in Stockholm November 4-5 1988 and had the title "The steroid/thyroid hoITIDne receptor family and gene regulation". This meeting contained contributions from most leading laboratories within the field of steroid/thyroid hOITIDne receptors and gave a very exciting perspective on the dynamic development of this i:ntx>rt. ant research field. Today all known steroid hoITIDne receptors have been cloned and sequenced and novel members of this supergene family are constantly being discovered. Sane of these new receptors remain to be characterized regarding the nature of their ligand. Access to probes for steroid receptors has enabled studies on mechanisms of regulation of receptor gene expression. Deletion and II'Altational analysis of steroid receptor cDNAs followed by expression in cells together with suitable reporter genes has yielded a detailed knowledge about the functional significance of the various domains the receptors are composed of. In certain cases, steroid resistance in patients have been shown to be due to point mutations in the corresponding steroid receptor genes resulting in non-functional receptors. The availability of receptor cDNAs also makes it possible to express receptors at high levels in procaryotic and eucaryotic cells. It is e. g. possible to express the DNA-binding domain of the glucocorticoid receptor in E. coli as a fusion protein with protein A which interacts specifically with DNA. Such studies are necessary for production of sufficient quantities of receptors to allow crystallization and X-ray crystallography for detailed structural information.

The Second International CBT (Center for Biotechnology) Synposium was held in Stockholm November 4-5 1988 and had the title "The steroid/thyroid hoITIDne receptor family and gene regulation". This meeting contained contributions from most leading laboratories within the field of steroid/thyroid hOITIDne receptors and gave a very exciting perspective on the dynamic development of this i:ntx>rt. ant research field. Today all known steroid hoITIDne receptors have been cloned and sequenced and novel members of this supergene family are constantly being discovered. Sane of these new receptors remain to be characterized regarding the nature of their ligand. Access to probes for steroid receptors has enabled studies on mechanisms of regulation of receptor gene expression. Deletion and II'Altational analysis of steroid receptor cDNAs followed by expression in cells together with suitable reporter genes has yielded a detailed knowledge about the functional significance of the various domains the receptors are composed of. In certain cases, steroid resistance in patients have been shown to be due to point mutations in the corresponding steroid receptor genes resulting in non-functional receptors. The availability of receptor cDNAs also makes it possible to express receptors at high levels in procaryotic and eucaryotic cells. It is e. g. possible to express the DNA-binding domain of the glucocorticoid receptor in E. coli as a fusion protein with protein A which interacts specifically with DNA. Such studies are necessary for production of sufficient quantities of receptors to allow crystallization and X-ray crystallography for detailed structural information.

The Second International CBT (Center for Biotechnology) Synposium was held in Stockholm November 4-5 1988 and had the title "The steroid/thyroid hoITIDne receptor family and gene regulation". This meeting contained contributions from most leading laboratories within the field of steroid/thyroid hOITIDne receptors and gave a very exciting perspective on the dynamic development of this i:ntx>rt. ant research field. Today all known steroid hoITIDne receptors have been cloned and sequenced and novel members of this supergene family are constantly being discovered. Sane of these new receptors remain to be characterized regarding the nature of their ligand. Access to probes for steroid receptors has enabled studies on mechanisms of regulation of receptor gene expression. Deletion and II'Altational analysis of steroid receptor cDNAs followed by expression in cells together with suitable reporter genes has yielded a detailed knowledge about the functional significance of the various domains the receptors are composed of. In certain cases, steroid resistance in patients have been shown to be due to point mutations in the corresponding steroid receptor genes resulting in non-functional receptors. The availability of receptor cDNAs also makes it possible to express receptors at high levels in procaryotic and eucaryotic cells. It is e. g. possible to express the DNA-binding domain of the glucocorticoid receptor in E. coli as a fusion protein with protein A which interacts specifically with DNA. Such studies are necessary for production of sufficient quantities of receptors to allow crystallization and X-ray crystallography for detailed structural information.

The first Meadowbrook Symposium was held in 1978 and during the intervening ten years our knowledge concerning how steroid hormones function at the level of gene expression has advanced by leaps and bounds. In this volume, which sum marizes our fourth meeting, these advances are very evident. What seemed like science fiction ten years ago has become commonplace science. Who would have imagined that we could synthesize a nucleotide sequence that binds a specific steroid receptor and acts as a controlling element for gene expression? No one; but as is evident from the results reported in several chapters, this technique is yielding a wealth of information. Using these and other techniques it has become apparent that gene transcription is controlled by interactions between transacting factors and DNA recognition sequences (response elements). These transacting factors appear to be members of a large gene family that includes steroid hormone receptors, transcription factors, protooncogenes and homeobox proteins. Thus a great deal has been learned, but as usual, questions remain. Many of these questions are posed by the findings and observations found in several chapters in this volume. Non hormone binding forms of steroid receptors and their relevance to receptor down regulation, recycling and biological response remain a mystery. The quantitative relationship between receptor binding and biological response still presents agonizing problems. These and many other intriguing questions are discussed in this volume and set the stage for what should be a most rewarding time in endocrinology. Winter 1989 ARUN K.

Intracellular Receptors: New Instruments for a Symphony of Signals In the late eighteenth century, it was proposed on theoretical grounds that each of the body's organs, beginning with the brain, must be "a factory and laboratory of a specific humor which it returns to the blood", and that these circulating signals "are indispensable for the life of the whole" (Bordeu 1775). During the nineteenth cen tury, some remarkable physiological experiments revealed the actions of humoral factors that affected the for and function of multiple tissues, organs and organ sys tems within the body (Berthold 1849); much later, the chemical and molecular na ture of some of those factors was determined. Against this deep historical backdrop of the founding studies of intercellular signaling, molecular biology sprang into existence a mere forty years ago, rooted in the revelation of regulable gene expression in bacteria. But contemporaneous with those classical analyses of transcriptional regulation of the lactose operon, the mod em era of signal transduction was inaugurated by the identification of cAMP as a second messenger -- an intracellular mediator of hormonal activation of glycogen catabolism (Sutherland and RaIl 1960). Later in that same decade, it emerged that cAMP is a critical signal not only in metazoans, but even in bacteria, where it serves an analogous function as a critical switch that activates expression of genes re quired for catabolism of complex carbon sources, including those of the lactose operon.

The past few years have witnessed the emergence of steroid hormones as the wonder molecules which generate as much discussion in the scientific literature as they do in a typical living room. This transition has been a result of the tremendous public and scientific interest in the normal functioning of the hor mones as well their suggested involvement in several clinical conditions. In the recent past, notable scientific and technological advances have been made in the areas of contraception and regulation of fertility. Steroid receptors are the indis pensable mediators of hormonal responses and are complex protein molecules which appear to exist in association with other, yet undefined, proteins and/or factors. Receptors for vitamin D, retinoic acid and the thyroid hormones share structural similarities with steroid receptors, and the roster of this superfamily is still expanding. While our knowledge of the diversity and magnitude of steroid effects has advanced, the precise mode of steroid hormone action has alluded investigators. This volume brings together an international team of prominent investigators who discuss their most recent work on the basic and clinical aspects of steroid/nuclear receptors. The contributions represent updated versions of the invited presentations made at The Second Meadow Brook Conference on Steroid Receptors in Health and Disease. I am grateful to my colleagues on the Scientific Committee: Etienne Baulieu, Jack Gorski, Benita Katzenellenbogen, David Toft and James WittJiff, who provided the vision and guidance in formulating an out standing program.