Steroid hormone receptors: Evolution, ligands, and molecular basis of biologic function

The characterization of the superfamily of nuclear receptors, in particular the steroid/retinoid/thyroid hormone receptors, has resulted in a more complete understanding of how a repertoire of hormonally and nutritionally derived lipophilic ligands controls cell functions to effect development and homeostasis. As transducers of hormonal signaling in the nucleus, this superfamily of DNA-binding proteins appears to represent a crucial link in the emergence of multicellular organisms. Because nuclear receptors bind and are conformationally activated by a chemically diverse array of ligands, yet are closely related in general structure, they present an intriguing example of paralogous evolution. It is hypothesized that an ancient prototype receptor evolved into an intricate set of dimerizing isoforms, capable of recognizing an ensemble of hormone-responsive element motifs in DNA, and exerting ligand-directed combinatorial control of gene expression. The effector domains of nuclear receptors mediate transcriptional activation by recruiting coregulatory multisubunit complexes that remodel chromatin, target the initiation site, and stabilize the RNA polymerase II machinery for repeated rounds of transcription of the regulated gene. Because some nuclear receptors also function in gene repression, while others are constitutive activators, this superfamily of proteins provides a number of avenues for investigating hormonal regulation of gene expression. This review surveys briefly the latest findings in the nuclear receptor field and identifies particular areas where future studies should be fruitful.