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Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor
1The Albert Einstein Comprehensive Cancer Center, Division of Hormone-Dependent Tumor Biology, Department of Developmental and Molecular Biology Albert Einstein College of Medicine Bronx, New York 10461, USA.
Abstract:
The androgen receptor (AR) is a ligand-regulated member of the nuclear receptor superfamily. The cyclin D1 gene product, which encodes the regulatory subunit of holoenzymes that phosphorylate the retinoblastoma protein (pRB), promotes cellular proliferation and inhibits cellular differentiation in several different cell types. Herein the cyclin D1 gene product inhibited ligand-induced AR- enhancer function through a pRB-independent mechanism requiring the cyclin D1 carboxyl terminus. The histone acetyltransferase activity of P/CAF (p300/CBP associated factor) rescued cyclin D1-mediated AR trans-repression. Cyclin D1 and the AR both bound to similar domains of P/CAF, and cyclin D1 displaced binding of the AR to P/CAF in vitro. These studies suggest cyclin D1 binding to the AR may repress ligand-dependent AR activity by directly competing for P/CAF binding.
Insights
Cyclin D1 inhibits androgen receptor (AR) activity by binding to P/CAF, a protein crucial for AR function. This interaction prevents AR from activating gene expression, suggesting a new mechanism for AR regulation.
Area of Science:
- Molecular Biology
- Cellular Biology
- Endocrinology
Background:
- The androgen receptor (AR) is a nuclear receptor regulating gene expression in response to androgens.
- Cyclin D1 is a cell cycle regulator that promotes proliferation and inhibits differentiation.
- AR signaling is critical in various physiological processes and diseases.
Purpose of the Study:
- To investigate the interaction between cyclin D1 and the androgen receptor (AR).
- To elucidate the mechanism by which cyclin D1 affects AR-mediated gene transcription.
- To explore the role of P/CAF in the regulation of AR activity by cyclin D1.
Main Methods:
- Reporter gene assays to measure AR-enhancer activity.
- Western blotting to assess protein interactions.
- In vitro binding assays to study protein complex formation.
- Analysis of cyclin D1 carboxyl terminus and pRB-independent mechanisms.
Main Results:
- Cyclin D1 inhibited ligand-induced AR-enhancer function via a pRB-independent pathway.
- The histone acetyltransferase P/CAF rescued cyclin D1-mediated AR trans-repression.
- Cyclin D1 and AR bound to similar domains of P/CAF.
- Cyclin D1 displaced AR binding to P/CAF in vitro.
Conclusions:
- Cyclin D1 represses ligand-dependent AR activity.
- This repression occurs through direct competition with AR for binding to P/CAF.
- The findings reveal a novel mechanism of AR regulation involving cyclin D1 and P/CAF.