title: Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP.
abstract: The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.
authors.affiliation: Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
authors.forename: Julianne
authors.initials: J
authors.lastname: Elvenes
authors.forename: Ernst Ivan Simon
authors.initials: EI
authors.lastname: Thomassen
authors.forename: Sylvia Sagen
authors.initials: SS
authors.lastname: Johnsen
authors.forename: Katrine
authors.initials: K
authors.lastname: Kaino
authors.forename: Eva
authors.initials: E
authors.lastname: Sjøttem
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D011944:Receptors, Androgen; D012097:Repressor Proteins; C114750:TCF20 protein, human; D014157:Transcription Factors