The scaffolding protein RACK1 interacts with androgen receptor and promotes cross-talk through a protein kinase C signaling pathway.

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.

• 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)

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

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)