The ubiquitin-specific protease USP10 modulates androgen receptor function

The role of the ubiquitin/proteasome system in degrading nuclear hormone receptors and regulating their transcriptional function has emerged in the last few years. We identified the ubiquitin-specific protease USP10 as part of DNA-bound androgen receptor (AR) complexes purified from nuclear extracts of PC-3 cells stably expressing the AR. The interaction between USPIO and the AR was confirmed by GST pull-down assays. Fluorescence microscopy documented that USPIO was localised in the nucleus and the cytoplasm. Cell-based transactivation assays in PC-3/AR cells revealed that overexpression of wild-type USPIO, but not of an enzymatically inactive form, stimulated AR activity mediated by reporter constructs harbouring selective androgen response elements (AREs), non-selective steroid response elements (SREs) or the mouse mammary tumour virus (MMTV) promoter. Conversely, USPIO expression knock-down by siRNAs impaired the MMTV response to androgen. In summary, the data indicate that USPIO is a new cofactor that binds to the AR and stimulates the androgen response of target promoters. This finding underlines the role of the ubiquitin/proteasome system in modulating the AR function. (c) 2005 Elsevier Ireland Ltd. All rights reserved.