Ligand-independent activation of steroid hormone receptors.
In addition to the conventional hormone-dependent regulation of the activity of steroid/thyroid receptor family members, many studies have shown that there is substantial cross-talk between signal transduction pathways and steroid receptors. In a number of cases the modulation of kinase/phosphatase activity in cells leads to activation of steroid receptors in the absence of hormone. This novel mechanism may not be ubiquitous as the glucocorticoid receptor appears to be refractory to activation in the absence of hormone. However, estrogen receptors, progesterone receptors, androgen receptors, retinoic acid receptors, retinoid X receptors, and vitamin D receptors all exhibit ligand-independent activation under appropriate conditions. Whether a steroid receptor responds to a signal by inducing transcription of a target gene in the absence of hormone depends upon the cell type, promoter, and activator. The mechanism(s) by which ligand-independent activation is induced is currently a subject of great interest. Because the signals that activate receptors induce protein phosphorylation, altered phosphorylation of the receptors, and/or proteins that associate with the receptors are likely to be key to ligand-independent activation. In the case of the estrogen receptor there is good evidence that altered receptor phosphorylation plays a role in ligand-independent activation. Other likely targets are proteins in the heat shock protein complexes, corepressors, and/or coactivators of steroid receptors.