Steroid hormone receptors

In the three decades since the original discovery of receptors for steroid hormones, much has been learned about the biochemical processes by which these regulatory agents exert their effects in target tissues. The intracellular receptor proteins are potential transcription factors, needed for optimal gene expression in hormone-dependent cells. They are present in an inactive form until association with the hormone converts them to a functional state that can react with target genes. Transformation of the receptor protein to the nuclear binding form appears to involve the removal of both macromolecular and micromolecular factors that act to keep the receptor form reacting with DNA. Much of the native receptor is present in the nucleus, loosely bound and readily extractable, but for some and possibly all steroid hormones, some receptor is in the cytoplasm, perhaps in equilibrium with a nuclear pool. Methods have been developed for the stabilization, purification, and characterization of receptor proteins, and through cloning and sequencing of their cDNAs, primary structures for these receptors are now known. This has led to the recognition of structural similarities among the family of receptors for the different steroid hormones and to the identification of regions in the protein molecule responsible for the various aspects of their function. Monoclonal antibodies recognizing specific molecular domains are available for most receptors. Despite the knowledge that has been acquired, many important questions remain unsolved. How does association with the steroid remove factors keeping the receptor protein in its native state, and how does binding of the transformed receptor to the response element in the promoter region enhance gene transcription? Once it has converted the receptor to the nuclear binding state, is there a further role for the steroid in modulating transcription? Still not entirely clear is the involvement of phosphorylation and/or dephosphorylation in hormone binding, receptor transformation, and transcriptional activation. Less vital to basic understanding but important in the overall picture is whether the native receptors for gonadal hormones are entirely confined to the nucleus or whether there is an intracellular distribution equilibrium. With the effort now being devoted to this field, and with the application of new experimental techniques, especially those of molecular biology, our understanding of receptor function is progressing rapidly. The precise mechanism of steroid hormone action should soon be completely established.