title: Rapid glucocorticoid receptor exchange at a promoter is coupled to transcription and regulated by chaperones and proteasomes.
abstract: Exchange of the glucocorticoid receptor (GR) at promoter target sites provides the only known system in which transcription factor cycling at a promoter is fast, occurring on a time scale of seconds. The mechanism and function of this rapid exchange are unknown. We provide evidence that proteasome activity is required for rapid GR exchange at a promoter. We also show that chaperones, specifically hsp90, stabilize the binding of GR to the promoter, complicating models in which the associated chaperone, p23, has been proposed to induce GR removal. Our results are the first to connect chaperone and proteasome functions in setting the residence time of a transcription factor at a target promoter. Moreover, our results reveal that longer GR residence times are consistently associated with greater transcriptional output, suggesting a new paradigm in which the rate of rapid exchange provides a means to tune transcriptional levels.
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute. Light Imaging Facility, National Institute for Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Stavreva
authors.forename: Waltraud G
authors.initials: WG
authors.lastname: Müller
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Smith
authors.forename: James G
authors.initials: JG
authors.lastname: McNally
mesh_terms: D000818:Animals; D016227:Benzoquinones; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D036681:Fluorescence Recovery After Photobleaching; D005938:Glucocorticoids / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D011809:Quinones / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D011809:Quinones; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D003345:Corticosterone; C001277:geldanamycin