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J. Biol. Chem., Vol. 277, Issue 33, 29719-29729, August 16, 2002
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From the Department of Biochemistry and Molecular Biology,
Georgetown University School of Medicine,
Washington, D. C. 20007
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
that 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.
Loss of Androgen Receptor Transcriptional Activity at the
G1/S Transition*
*
This work was supported by Department of Defense predoctoral
fellowship DAMD17-99-1-9199 (to E. M.) and by American Heart Association (Mid-Atlantic) Grant 9951256U (to M. D.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Biochemistry
and Molecular Biology, Georgetown University School of Medicine, Basic
Science Bldg. Rm. 355, 3900 Reservoir Rd., NW, Washington, D. C.
20007. Tel.: 202-687-4169; Fax: 202-687-7186; E-mail:
dan@bc.georgetown.edu.
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