Steroid hormone receptors: an update

Human Reproduction Update 2000, Vol. 6 No. 3 pp. 225–236 © European Society of Human Reproduction and Embryology Steroid hormone receptors: an update M.Beato* and J.Klug Institut für Molekularbiologie und Tumorforschung, IMT, Philipps-Universität, 35033 Marburg, Germany Received on August 26, 1999; accepted on February 28, 2000 Steroid hormones (SHs) are lipophilic molecules derived from cholesterol and synthesized in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, oestrogen), and the ovary and placenta (oestrogens and progestagens or progestins). SHs reach their target cells via the blood, where they are bound to carrier proteins, and because of their lipophilic nature pass the cell membrane by simple diffusion. Within the target cells SHs bind to steroid hormone receptors (SHRs), the key mediators of SH action, which are complexed to chaperones, e.g. heat shock protein 90 (Hsp90), that help other proteins to fold and prevent aggregation. SHRs are intracellular transcription factors that can be activated, among other possibilities, by the specific and high affinity binding of ligand to exert positive or negative effects on the expression of target genes. Binding of agonistic or antagonistic ligands leads to different allosteric changes of SHRs making them competent to exert positive or negative effects on the expression of target genes by different mechanisms. (i) After dissociation of chaperones the liganded SHR–complexes can bind to chromatin organized DNA sequences in the vicinity of target genes, termed hormone response elements (HREs). The HRE-recruited hormone-receptor-complexes are then able to initiate chromatin remodelling and to relay activating or repressing signals to the target genes transcription machinery; (ii) through protein–protein interactions with other sequence-specific transcription factors, SHRs can also regulate the activity of many genes that are switched on, for instance, during stress or an inflammatory response; (iii) the SH response can also be integrated in the intracellular signalling network via cross-talk of SHRs with signal transduction pathways that transmit extracellular signals via membrane receptors and activation of protein kinase cascades to nuclear transcription factors that activate various target genes. By all these different mechanisms SHRs modulate numerous and specific responses in a large variety of cells, whereby their particular effect depends on the physiological, cellular and genetic context. Key words: chromatin/cross-talk/steroid hormones/steroid hormone receptors/transcription factors TABLE OF CONTENTS Introduction Domain structure of steroid hormone receptors Receptor isoforms and variants DNA and chromatin binding Ligand binding Activation of transcription Cross-talk with other signal transduction pathways Conclusions Acknowledgements References 225 226 227 228 230 230 233 233 234 234 Introduction In mammals the gonads and adrenal gland produce five major groups of steroid hormones (SHs): oestrogens, progestins, androgens, glucocorticoids and mineralocorticoids. All these SHs regulate a large number of physiological processes in target cells equipped with the corresponding steroid hormone receptors (SHRs). The concept of target cells has been extended in the last years following the demonstration of functional SHRs in a large variety of cell types. For these, and many other crucial experiments, the availability of radioactively labelled SHs in the late 1950s was a key development. Using these compounds it was possible to follow the fate of the steroid hormones from their site of synthesis in the endocrine glands, through the blood circulation, up to their target tissues (Jensen and Jacobsen, 1962). Although SHs are extensively metabolized, particularly in the liver, it could be shown that in most cases the hormone itself, not a metabolite, produced the response via the modulation of gene expression mechanisms. The concept that steroid hormones are involved in transcriptional control was triggered by the observation that the insect steroid hormone ecdysone induces puffs in giant chromosomes (Clever and Karlson, 1960). A few years later, a two-step model was established that involved binding of the hormone to specific high-affinity SHRs within the target cells, followed by activation of the hormone–receptor complex in order to induce expression of hormone responsive genes (Noteboom and * To whom correspondence should be addressed at Institut für Molekularbiologie und Tumorforschung, IMT, Philipps-Universität, 35033 Marburg, Germany. Phone: +49 6421 286 62 86; Fax: +49 6421 286 53 98; E-mail: 226 M.Beato and J.Klug Figure 1. Trivial and nomenclature names of steroid hormone receptors (SHRs), according to the Nuclear Receptors Nomenclature Committee (1999). Current information can be found on the Nuclear Receptor Nomenclature Homepage (http://www.ens-lyon.fr/LBMC/LAUDET/nomenc.html). In manuscripts dealing with SHRs, it is recommended that the receptor(s) be identified by the official nomenclature at least once in the Summary and the Introduction. The three subgroups A, B and C are separated by stippled lines. Genebank accession numbers are given for the human mRNAs, except for NR3A2, which is from the rat. Gorski, 1965; Jensen et al., 1968). Almost 20 years later the receptors for glucocorticoids and oestrogens were cloned and thus became the first molecularly-defined transcription factors for RNA polymerase II (Hollenberg et al., 1985; Walter et al., 1985; Weinberger et al., 1985a,b). At around the same time cloned SHR targets, e.g. human metallothionein gene and the mouse mammary tumour virus (MMTV) were used in DNA binding and gene transfer experiments to identify the first hormone response elements (HREs) (Chandler et al., 1983; Payvar et al., 1983; Scheidereit et al., 1983; Karin et al., 1984). HREs are short DNA sequence elements that convey direct transcriptional responsiveness to adjacent genes. During the last decade many details of the SHR signal transduction pathway, including new mechanisms, have been discovered. In this review we will summarize our present view of the various pathways by which SHRs modulate gene expression. Domain structure of SHRs Following the cloning of the receptors for glucocorticoids (GR) and oestrogens (ERα), receptors for androgens (AR), progestins (PR) and mineralocorticoids (MR) have been identified and extensively characterized. More recently, a second oestrogen receptor (ERβ) and two oestrogen-related receptors (ERRα/ERR1 and ERRβ/ERR2) have been characterized. All SHRs are characterized by a central DNA-binding domain (DBD), that targets the receptor to the HREs, and a ligand-binding domain (LBD), required for switching the receptors’ functions (Beato, 1989). When the v-erbA oncogene was cloned it turned out to contain also a DBD and an LBD that were homologous to the cognate regions of the (...truncated)