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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.

Original publication

DOI

10.1074/jbc.M306219200

Type

Journal article

Journal

J Biol Chem

Publication Date

14/11/2003

Volume

278

Pages

46087 - 46093

Keywords

Active Transport, Cell Nucleus, Animals, Blotting, Western, COS Cells, Cell Differentiation, Cell Division, Cell Line, Tumor, Chromatin, Gene Deletion, Humans, Indoles, Lactams, Ligands, Microscopy, Fluorescence, Peptides, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Kinase C, Protein Structure, Tertiary, RNA, Messenger, Receptors, Androgen, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transcription, Genetic, Transcriptional Activation, Two-Hybrid System Techniques, beta-Galactosidase