title: Ski-interacting protein (SKIP) interacts with androgen receptor in the nucleus and modulates androgen-dependent transcription.
abstract: BACKGROUND
  The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily of ligand-inducible DNA transcription factors, and is the major mediator of male sexual development, prostate growth and the pathogenesis of prostate cancer. Cell and gene specific regulation by the AR is determined by availability of and interaction with sets of key accessory cofactors. Ski-interacting protein (SKIP; SNW1, NCOA62) is a cofactor shown to interact with several NRs and a diverse range of other transcription factors. Interestingly, SKIP as part of the spliceosome is thought to link mRNA splicing with transcription. SKIP has not been previously shown to interact with the AR.
  
  
  RESULTS
  The aim of this study was to investigate whether SKIP interacts with the AR and modulates AR-dependent transcription. Here, we show by co-immunoprecipitation experiments that SKIP is in a complex with the AR. Moreover, SKIP increased 5α-dihydrotestosterone (DHT) induced N-terminal/C-terminal AR interaction from 12-fold to almost 300-fold in a two-hybrid assay, and enhanced AR ligand-independent AF-1 transactivation. SKIP augmented ligand- and AR-dependent transactivation in PC3 prostate cancer cells. Live-cell imaging revealed a fast (half-time=129 s) translocation of AR from the cytoplasm to the nucleus upon DHT-stimulation. Förster resonance energy transfer (FRET) experiments suggest a direct AR-SKIP interaction in the nucleus upon translocation.
  
  
  CONCLUSIONS
  Our results suggest that SKIP interacts with AR in the nucleus and enhances AR-dependent transactivation and N/C-interaction supporting a role for SKIP as an AR co-factor.
authors.affiliation: University of Queensland, Obesity Research Centre, Institute for Molecular Bioscience, St,Lucia, Queensland, 4072, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abankwa
authors.forename: Susan M
authors.initials: SM
authors.lastname: Millard
authors.forename: Nick
authors.initials: N
authors.lastname: Martel
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Choong
authors.forename: Miao
authors.initials: M
authors.lastname: Yang
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Ueki
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hayman
authors.forename: Gary M
authors.initials: GM
authors.lastname: Leong
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D013196:Dihydrotestosterone / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D056918:Nuclear Receptor Coactivators / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D056918:Nuclear Receptor Coactivators; D011944:Receptors, Androgen; C111791:SNW1 protein, human; D013196:Dihydrotestosterone