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Nucleic Acids Research 2005 33(1):13-26; doi:10.1093/nar/gki141
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Published online 7 January 2005

© 2005, the authors Nucleic Acids Research, Vol. 33 No. 1 © Oxford University Press 2005; all rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use permissions, please contact journals.permissions{at}oupjournals.org.

Article

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation

Luke Gaughan, Ian R. Logan, David E. Neal1 and Craig N. Robson*

Prostate Research Group, Northern Institute for Cancer Research Paul, O'Gorman Building University of Newcastle Upon Tyne, Medical School Framlington Place, Newcastle Upon Tyne NE2 4HH, UK 1 MRC Cancer Cell Unit, University of Cambridge Cambridge CB2 2X2, UK

*To whom correspondence should be addressed. Tel: +44 191 222 4266; Fax: +44 191 222 4301; Email: c.n.robson{at}ncl.ac.uk

Received November 12, 2004. Revised December 1, 2004. Accepted December 1, 2004.

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.


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