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Molecular and Cellular Biology, April 2004, p. 2682-2697, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2682-2697.2004

Rapid Glucocorticoid Receptor Exchange at a Promoter Is Coupled to Transcription and Regulated by Chaperones and Proteasomes

Diana A. Stavreva,1 Waltraud G. Müller,1 Gordon L. Hager,1 Carolyn L. Smith,2 and James G. McNally1*

Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute,1 Light Imaging Facility, National Institute for Neurological Disorders and Stroke, Bethesda, Maryland 208922

Received 29 July 2003/ Returned for modification 17 September 2003/ Accepted 10 December 2003

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.

* Corresponding author. Mailing address: 41 Library Dr., Bethesda, MD 20892. Phone: (301) 402-0209. Fax: (301) 496-4951. E-mail: mcnallyj{at}exchange.nih.gov.

Molecular and Cellular Biology, April 2004, p. 2682-2697, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2682-2697.2004




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