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Molecular and Cellular Biology, March 2007, p. 1823-1843, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01297-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ligand-Specific Dynamics of the Androgen Receptor at Its Response Element in Living Cells{triangledown}

Tove I. Klokk,1,{dagger} Piotr Kurys,1,{dagger} Cem Elbi,2,{ddagger} Akhilesh K. Nagaich,2,§ Anindya Hendarwanto,2 Thomas Slagsvold,1 Ching-Yi Chang,3 Gordon L. Hager,2* and Fahri Saatcioglu1*

Department of Molecular Biosciences, University of Oslo, Postboks 1041 Blindern, 0316 Oslo, Norway,1 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, Maryland 20892,2 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 277103

Received 14 July 2006/ Returned for modification 24 August 2006/ Accepted 8 December 2006

Androgens have key roles in normal physiology and in male sexual differentiation as well as in pathological conditions such as prostate cancer. Androgens act through the androgen receptor (AR), which is a ligand-modulated transcription factor. Antiandrogens block AR function and are widely used in disease states, but little is known about their mechanism of action in vivo. Here, we describe a rapid differential interaction of AR with target genomic sites in living cells in the presence of agonists which coincides with the recruitment of BRM ATPase complex and chromatin remodeling, resulting in transcriptional activation. In contrast, the interaction of antagonist-bound or mutant AR with its target was found to be kinetically different: it was dramatically faster, occurred without chromatin remodeling, and resulted in the lack of transcriptional inhibition. Fluorescent resonance energy transfer analysis of wild-type AR and a transcriptionally compromised mutant at the hormone response element showed that intramolecular interactions between the N and C termini of AR play a key functional role in vivo compared to intermolecular interactions between two neighboring ARs. These data provide a kinetic and mechanistic basis for regulation of gene expression by androgens and antiandrogens in living cells.

* Corresponding author. Mailing address for Fahri Saatcioglu: Department of Molecular Biosciences, University of Oslo, Postboks 1041 Blindern, 0316 Oslo, Norway. Phone: 47-22854569. Fax: 47-22857207. E-mail: fahris{at}imbv.uio.no. Mailing address for Gordon L. Hager: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 496-9867. Fax: (301) 496-4951. E-mail: hagerg{at}dce41.nci.nih.gov.

{triangledown} Published ahead of print on 22 December 2006.

{dagger} T.I.K and P.K. contributed equally to this work.

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

§ Present address: Division of Therapeutic Proteins, CDER, FDA, Bethesda, MD 20892.

Molecular and Cellular Biology, March 2007, p. 1823-1843, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01297-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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