Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / genetics
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14-3-3 Proteins / metabolism
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14-3-3 Proteins / physiology*
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Androgens / pharmacology*
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Blotting, Western
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Humans
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Luciferases / genetics
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Luciferases / metabolism
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Male
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Metribolone / pharmacology
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Prostate-Specific Antigen / genetics
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Prostate-Specific Antigen / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Isoforms / physiology
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RNA, Small Interfering / genetics
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Receptors, Androgen / genetics*
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Receptors, Androgen / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Transcription, Genetic / drug effects*
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Transfection
Substances
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14-3-3 Proteins
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Androgens
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Protein Isoforms
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RNA, Small Interfering
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Receptors, Androgen
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Recombinant Fusion Proteins
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Metribolone
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Luciferases
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Prostate-Specific Antigen