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Papers In Press, published online ahead of print June 7, 2002
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007
Corresponding Author: dan{at}bc.georgetown.edu
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 G1/S boundary. In S-phase, the receptor regains activity, indicating that there is a transient regulatory event that inactivates the AR at the G1/S transition. This regulation is specific for the AR, since the related glucocorticoid receptor is transcriptionally active at the G1/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 G1/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 G1/S boundary, demonstrating the involvement of acetylation pathways in the cell cycle regulation of AR transcriptional activity. Finally, a model is proposed which explains the inactivity of the AR at the G1/S transition by integrating receptor levels, the action of cell-cycle regulators and the contribution of histone acetyltransferase-containing coactivators.
J. Biol. Chem, 10.1074/jbc.M112134200
Submitted on December 19, 2001
Revised on May 17, 2002
Accepted on June 7, 2002
Loss of androgen receptor transcriptional activity at the G1/S transition
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