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Transcriptional Activity of Androgen Receptor Is Modulated by Two RNA Splicing Factors, PSF and p54nrb

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, Canada M5G 1X5,¹ University Health Network, University of Toronto, 200 Elizabeth Street, Toronto, Canada M5G 2M9,² Department of Physiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Canada M5S 1A8³

Received 15 November 2006/ Returned for modification 16 January 2007/ Accepted 11 April 2007

Nuclear receptors regulate gene activation or repression through dynamic interactions with coregulators. The interactions between nuclear receptors and RNA splicing factors link gene transcription initiation with pre-mRNA splicing, providing a coordinated control of the products of gene transcription. Here we report that two RNA splicing factors, PTB-associated splicing factor (PSF) and p54nrb, synergistically form protein complexes with the androgen receptor (AR) in a ligand-independent manner and inhibit its transcriptional activity. PSF does not affect AR protein stability, as in the case of the progesterone receptor, but impedes the interaction of AR with the androgen response element. Both splicing factors interact directly with mSin3A and attract mSin3A to the AR complex in a synergistic manner. The suppression of AR transcriptional activity by PSF and p54nrb is reversed by the inhibition of histone deacetylase activity. These data demonstrated that PSF and p54nrb complex with AR and play a key role in modulating AR-mediated gene transcription.

Published ahead of print on 23 April 2007.