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Molecular and Cellular Biology, April 2007, p. 2442-2451, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01570-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Ligand Binding Domain Controls Glucocorticoid Receptor Dynamics Independent of Ligand Release{triangledown}

Sebastiaan H. Meijsing,1 Cem Elbi,2,{dagger} Hans F. Luecke,1 Gordon L. Hager,2 and Keith R. Yamamoto1*

Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California 94107,1 Laboratory of Receptor Biology and Gene Expression, National Institutes of Health, Bethesda, Maryland 208922

Received 22 August 2006/ Returned for modification 16 October 2006/ Accepted 8 January 2007

Ligand binding to the glucocorticoid receptor (GR) results in receptor binding to glucocorticoid response elements (GREs) and the formation of transcriptional regulatory complexes. Equally important, these complexes are continuously disassembled, with active processes driving GR off GREs. We found that cochaperone p23-dependent disruption of GR-driven transcription depended on the ligand binding domain (LBD). Next, we examined the importance of the LBD and of ligand dissociation in GR-GRE dissociation in living cells. We showed in fluorescence recovery after photobleaching studies that dissociation of GR from GREs is faster in the absence of the LBD. Furthermore, GR interaction with a target promoter revealed ligand-specific exchange rates. However, using covalently binding ligands, we demonstrated that ligand dissociation is not required for receptor dissociation from GREs. Overall, these studies showed that activities impinging on the LBD regulate GR exchange with GREs but that the dissociation of GR from GREs is independent from ligand dissociation.

* Corresponding author. Mailing address: Department of Cellular and Molecular Pharmacology, University of California-San Francisco, 600 16th Street, Room GH-S574, San Francisco, CA 94107-2280. Phone: (415) 476-3128. Fax: (415) 476-6129. E-mail: yamamoto{at}cmp.ucsf.edu.

{triangledown} Published ahead of print on 29 January 2007.

{dagger} Present address: Merck Research Laboratories, Boston, MA 02115.

Molecular and Cellular Biology, April 2007, p. 2442-2451, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01570-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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