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 com plete understanding of how a repertoire of hormonally and nutritionally der ived lipophilic ligands controls cell functions to effect development and h omeostasis. As transducers of hormonal signaling in the nucleus, this super family of DNA-binding proteins appears to represent a crucial link in the e mergence of multicellular organisms. Because nuclear receptors bind and are conformationally activated by a chemically diverse array of ligands, yet a re closely related in general structure, they present an intriguing example of paralogous evolution. It is hypothesized that an ancient prototype rece ptor evolved into an intricate set of dimerizing isoforms, capable of recog nizing an ensemble of hormone-responsive element motifs in DNA, and exertin g ligand-directed combinatorial control of gene expression. The effector do mains of nuclear receptors mediate transcriptional activation by recruiting coregulatory multisubunit complexes that remodel chromatin, target the ini tiation site, and stabilize the RNA polymerase II machinery for repealed ro unds of transcription of the regulated gene.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 far investigati ng hormonal regulation of gene expression. This review surveys briefly the latest findings in the nuclear receptor field and identifies particular are as where future studies should be fruitful. (C) 1999 Wiley-Liss, Inc.