Ligand-specific dynamics of the androgen receptor at its response element in living cells

Department of Molecular Biosciences, University of Oslo, Postboks 1041 Blindern, 0316 Oslo, Norway.
Molecular and Cellular Biology (Impact Factor: 5.04). 04/2007; 27(5):1823-43. DOI: 10.1128/MCB.01297-06
Source: PubMed

ABSTRACT 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.

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Available from: Nagaich Akhilesh, Aug 23, 2015
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    • "In addition to preventing androgen binding to the AR as an antagonist, it has been suggested that bicalutamide induces release of cytochrome C by Bax-dependent and -independent mechanisms resulting in apoptosis of LNCaP cells [40]. Furthermore, previous work from our laboratory suggests that AR antagonists, including bicalutamide, may function by affecting AR–chromatin interaction dynamics [50]. Further work is required to determine at what level bicalutamide and the PI3K/Akt/mTOR pathway interact to bring about the added inhibitory effects on prostate cancer cells. "
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