Glucocorticoid receptor: Translocation from the cytoplasm to the nuclei; chromatin and intranuclear chaperone cycles

A glucocorticoid receptor (GR) is a ligand-dependent transcription factor involved in the regulation of hundreds of genes. In the absence of any ligand, the GR resides in the cytoplasm where it is sequestered in a multimeric chaperone complex consisting of hsp90, hsp70, p23, Hop, FKBP51, FKBP52, etc. As part of this multiprotein complex, the GR undergoes conformational changes that make it resemble glucocorticoids. Upon ligand binding, the GR is dissociated from the chaperone complex and migrates into the nucleus, where it interacts with specific DNA sequences (GREs) in the regulatory regions of target genes and modulates their expression. Then the hormone-free GR is exported to the cytoplasm to complete its nuclearcytoplasmic cycle. The recent evidence suggests that, in addition to this cycle, chromatin and chaperone GR cycles exist within the nuclei. The chromatin cycle implies repeated interactions of the ligand-bound GR with the GREs in the chromatin context lasting for few seconds. The chaperone cycle starts after dissociation of the hormone–receptor complex, when the GR is bound to the same chaperones that interact with it in the cytoplasm. As a result, its hormone-binding affinity is regained. Upon hormone binding, the GR is dissociated from the chaperone complex and again attaches itself to the GREs. It is assumed that the chaperone cycle is mainly responsible for prolonged GR retention in the nuclei, for several hours. In this review, we summarize and critically analyze the published data on the chromatin and intranuclear chaperone cycles of the GR.