14-3-3 sigma increases the transcriptional activity of the androgen receptor in the absence of androgens.
The androgen receptor (AR) is a ligand-activated transcription factor that regulates numerous target genes, including prostate-specific antigen (PSA). We examined the ability of each member of the 14-3-3 family to modulate transcription of PSA through the AR. Despite significant homology within the 14-3-3 family we observed differences in the ability of each isoform to alter the transcriptional activity of the AR. Significantly, 14-3-3 sigma activated PSA-luciferase reporters not only at castrate levels of androgens, but also in the complete absence of androgens. 14-3-3 sigma also increased expression of the endogenous PSA gene in the absence of androgens. Knockdown of the AR by siRNA oligonucleotides abolished activation of these reporters by 14-3-3 sigma. These findings may have greatest significance in hormone refractory prostate cancer where the AR may be activated in a ligand-independent manner.
Quayle
Steven N
SN
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
Sadar
Marianne D
MD
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000728:Androgens / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D048948:14-3-3 Proteins; D000728:Androgens; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D015741:Metribolone; D008156:Luciferases; D017430:Prostate-Specific Antigen