Homologous down regulation of the glucocorticoid receptor: the molecular machinery

The biological action of glucocorticoids is mediated by intracellular glucocorticoid receptors (GR) that, when bound by homologous ligand, function as DNA-binding proteins that enhance or repress basal transcription rates of responsive genes. The cellular sensitivity to glucocorticoids is directly proportional to the receptor concentration. In most cells, glucocorticoids promote a reduction in GR levels by a process termed homologous down regulation. This ligand-induced, receptor-mediated event consequently limits the span of cellular responsiveness to glucocorticoids. In the last decade, the molecular mechanisms underlying GR down regulation have been the subject of many reports. The consensus of these studies is that both a decrease in transcription of the GR gene and a posttranslational increase in receptor turnover contribute to the reduction in receptor concentration. There is considerably less agreement as to whether a posttranscriptional alteration in GR mRNA stability is also involved. The current thrust of GR down regulation research seeks to identify cis-elements within the receptor gene that are crucial for the decrease in GR mRNA synthesis and to determine the role, if any, other signal transduction pathways play in modulating the desensitizing process.