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J Biol Chem. 2002 Aug 16;277(33):29719-29. Epub 2002 Jun 7.

Loss of androgen receptor transcriptional activity at the G(1)/S transition.

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  • 1Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, D. C. 20007, USA.

Abstract

Androgens are essential for the differentiation, growth, and maintenance of male-specific organs. The effects of androgens in cells are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily of transcription factors. Recently, transient transfection studies have shown that overexpression of cell cycle regulatory proteins affects the transcriptional activity of the AR. In this report, we characterize the transcriptional activity of endogenous AR through the cell cycle. We demonstrate that in G0, AR enhances transcription from an integrated steroid-responsive mouse mammary tumor virus promoter and also from an integrated androgen-specific probasin promoter. This activity is strongly reduced or abolished at the G(1)/S boundary. In S phase, the receptor regains activity, indicating that there is a transient regulatory event that inactivates the AR at the G(1)/S transition. This regulation is specific for the AR, since the related glucocorticoid receptor is transcriptionally active at the G(1)/S boundary. Not all of the effects of androgens are blocked, however, since androgens retain the ability to increase AR protein levels. The transcriptional inactivity of the AR at the G(1)/S junction coincides with a decrease in AR protein level, although activity can be partly rescued without an increase in receptor. Inhibition of histone deacetylases brings about this partial restoration of AR activity at the G(1)/S boundary, demonstrating the involvement of acetylation pathways in the cell cycle regulation of AR transcriptional activity. Finally, a model is proposed that explains the inactivity of the AR at the G(1)/S transition by integrating receptor levels, the action of cell cycle regulators, and the contribution of histone acetyltransferase-containing coactivators.

PMID:
12055183
[PubMed - indexed for MEDLINE]
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