Adrenal and sex steroid receptor evolution: environmental implications

The nuclear receptor family responds to a diverse group of ligands, includi ng steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. Pr evious sequence analyses of adrenal and sex steroid receptors indicate that they form a clade separate from other nuclear receptors. However, the rela tionships of adrenal and sex steroid receptors to each other and to their a ncestors are not fully understood. We have used new information from androg en, estrogen, mineralocorticoid and progesterone receptors in fish to bette r resolve the phylogeny of adrenal and sex steroid receptors. Sequence dive rgence between fish and mammalian steroid receptors correlates with differe nces in steroid specificity, suggesting that phylogeny needs to be consider ed in evaluating the endocrine effects of xenobiotics. Among the vertebrate steroid receptors, the most ancient is the estrogen receptor. The phylogen y indicates that adrenal and sex steroid receptors arose in a jawless fish or a protochordate and that changes in the sequence of the hormone-binding domain have slowed considerably in land vertebrates. The retinoid X recepto r clade is closest to the adrenal and sex steroid receptor clade. Retinoid X receptor is noteworthy for its ability to form dimers with other nuclear receptors,' an important mechanism for regulating the action of retinoid X receptor and its dimerization partners. In contrast, the adrenal and sex st eroid receptors bind to DNA as homodimers. Moreover, unliganded adrenal and sex steroid receptors form complexes with heat shock protein 90. Thus, the evolution of adrenal and sex steroid receptors involved changes in protein -protein interactions as well as ligand recognition.