Steroid hormone receptors: an update.

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.