Abstract |
The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, functions as a ligand-dependent transcription factor that regulates genes involved in cell proliferation and differentiation. Using a C-terminal region of the human AR in a yeast two-hybrid screen, we have identified RACK1 ( receptor for activated C kinase-1) as an AR-interacting protein. In this report we found that RACK1, which was previously shown to be a protein kinase C (PKC)-anchoring protein that determines the localization of activated PKCbetaII isoform, facilitates ligand-independent AR nuclear translocation upon PKC activation by indolactam V. We also observed RACK1 to suppress ligand-dependent and -independent AR transactivation through PKC activation. In chromatin immunoprecipitation assays, we demonstrate a decrease in AR recruitment to the AR-responsive prostate-specific antigen (PSA) promoter following stimulation of PKC. Furthermore, prolonged exposure to indolactam V, a PKC activator, caused a reduction in PSA mRNA expression in prostate cancer LNCaP cells. Finally, we found PKC activation to have a repressive effect on AR and PSA protein expression in androgen-treated LNCaP cells. Our data suggest that RACK1 may function as a scaffold for the association and modification of AR by PKC enabling translocation of AR to the nucleus but rendering AR unable to activate transcription of its target genes.
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Authors | Anastasia C Rigas, Daniel M Ozanne, David E Neal, Craig N Robson |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 278
Issue 46
Pg. 46087-93
(Nov 14 2003)
ISSN: 0021-9258 [Print] United States |
PMID | 12958311
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chromatin
- Indoles
- Lactams
- Ligands
- Peptides
- Protein Isoforms
- RNA, Messenger
- Receptors for Activated C Kinase
- Receptors, Androgen
- peptide I
- indolactam V
- Protein Kinase C
- beta-Galactosidase
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Topics |
- Active Transport, Cell Nucleus
- Animals
- Blotting, Western
- COS Cells
- Cell Differentiation
- Cell Division
- Cell Line, Tumor
- Chromatin
(metabolism)
- Gene Deletion
- Humans
- Indoles
(pharmacology)
- Lactams
(pharmacology)
- Ligands
- Microscopy, Fluorescence
- Peptides
(chemistry, metabolism)
- Precipitin Tests
- Protein Binding
- Protein Isoforms
- Protein Kinase C
(metabolism)
- Protein Structure, Tertiary
- RNA, Messenger
(metabolism)
- Receptors for Activated C Kinase
- Receptors, Androgen
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Time Factors
- Transcription, Genetic
- Transcriptional Activation
- Two-Hybrid System Techniques
- beta-Galactosidase
(metabolism)
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