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 USP10 and the AR was confirmed by GST pull-down assays. Fluorescence microscopy documented that USP10 was localised in the nucleus and the cytoplasm. Cell-based transactivation assays in PC-3/AR cells revealed that overexpression of wild-type USP10, 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, USP10 expression knock-down by siRNAs impaired the MMTV response to androgen. In summary, the data indicate that USP10 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.
Faus
Hortensia
H
Corporate Research Oncology, Schering AG, D-13342 Berlin, Germany.
Meyer
Hellmuth-Alexander
HA
Huber
Martina
M
Bahr
Inke
I
Haendler
Bernard
B
D000728:Androgens / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D004273:DNA, Neoplasm / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D020218:Response Elements / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D043222:Ubiquitin Thiolesterase
C410798:AR protein, human; D000728:Androgens; D004273:DNA, Neoplasm; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C431363:USP10 protein, human; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase