Part of “CHAPTER 73 – CORTICOSTEROID ACTION“

The steroid hormones, vitamin D, retinoic acid, and the thyroid hormones all share a similar mechanism of action.1,2 These hormones diffuse through the target cell membrane and interact with a specific receptor protein for each hormone. The activated hormone-receptor complex binds to specific DNA sequences, the hormone-responsive elements (HREs), which are usually located in the 5′ flanking region of each hormone-responsive gene. These complexes may also bind to other transcription factors. The binding of the hormone-receptor complex to these DNA sequences or transcription factors leads to selective increases or decreases in gene transcription. The altered protein levels that result from this change in transcription rate are responsible for the hormonal response seen in that particular tissue.3

At least six classes of steroid receptors exist, corresponding to the known bioactivities of the steroid hormones: glucocorticoid, mineralocorticoid, progestin, estrogen, androgen, and vitamin D. Additional “orphan” receptors of incompletely understood function are found that bind related compounds such as androstanes.4 Steroid receptors belong to a larger superfamily of nuclear transcriptional factors that includes the thyroid hormone and retinoic acid receptors. All of these receptors share a common structure that includes a carboxy-terminal ligand-binding domain and a midregion DNA-binding domain. The latter domain contains two “zinc fingers,” each of which consists of a loop of amino acids stabilized by four cysteine residues chelating a zinc ion.5

Unliganded steroid hormone receptors shuttle between the cytoplasm and the cell nucleus. Importation into the nucleus is an energy-dependent process. This process requires one or more nuclear localization signal sequences on the receptor, which consist of clusters of basic amino-acid residues located in or near the DNA-binding domain. When not occupied by ligand, the various hormone receptors differ in their propensity to be transported to the nucleus. For example, the estrogen receptor is predominantly located within the nucleus, whereas the unoccupied glucocorticoid and mineralocorticoid receptors are found mainly in the cytosol.6

The cytosolic glucocorticoid receptor, when not bound to its steroid ligand, forms a heterooligomer with two molecules of heat shock protein (HSP) 90 and one molecule each of HSP 70 and HSP 56 (immunophilin).7 Binding of ligand changes the conformation of the receptor and, thus, has several effects. HSP 90 is associated with the unliganded glucocorticoid receptor at the ligand-binding domain and dissociates from the receptor complex after glucocorticoid binds to the receptor. A dimerization region that overlaps the steroid-binding domain is exposed, promoting dimerization of the occupied receptor. Finally, a hormone-dependent nuclear localization signal located in a “hinge” between the DNA and steroid-binding domains is activated, which leads to increased importation of occupied receptors into the nucleus. The occupied receptors are then able to bind DNA and/or other transcription factors and modulate transcription of various genes.8,9