The steroid receptor superfamily: mechanisms of diversity.

The steroid receptor superfamily of ligand-dependent transcription factors is characterized by marked conservation of both structure and function between the various receptors. Despite their well-documented extensive similarities, these receptors respond to a diverse range of ligands, which results in an even more impressive diversity of function. A variety of strategies is used at each point in the pathway from ligand binding to gene expression to achieve this diversity. The nature of the ligand is important as are the tissue-specific patterns of receptor gene expression, the presence of binding proteins, and the effects of cell- or tissue-specific ligand-modifying enzymes. Once bound to the receptor, the nature of which may vary as a result of either differential splicing or gene duplication yielding multiple isoforms, the activated receptor may form hetero- or homodimers. A complex interplay then occurs between the receptor dimer, other nuclear proteins, the response element, and the promoter complex to regulate gene expression. These elements may vary as a function of the cell type, other stimuli, and the context and sequence of the response element (or elements) in a given gene. By these mechanisms diversity may even be achieved for a given ligand, receptor subtype, gene, or cell. The observations may help to explain certain phenomena in hormone biology that are difficult to reconcile with the previous, simple, univariant model of steroid hormone action.