Cyclin D1 binding to the androgen receptor (AR) NH2-terminal domain inhibits activation function 2 association and reveals dual roles for AR corepression.
The androgen receptor (AR) is a member of the nuclear receptor superfamily, the activity of which is critical for the development and progression of prostate cancer. We and others have previously demonstrated that cyclin D1 is a potent corepressor of the AR. Although cyclin D1 is suspected to recruit histone deacetylases to the AR complex, previous studies have demonstrated that this activity alone is insufficient for cyclin D1 function. Here, we uncover a novel, secondary means of cyclin D1-mediated repression, through modulation of AR amino-carboxy terminal interactions. We show that cyclin D1 predominantly binds the N-terminal domain of the AR, dependent on the AR 23FxxLF27 motif. Through this motif, cyclin D1 abrogates the ability of the AR N-terminal domain to interact with the C terminus. Secondary amino-terminal domain sites capable of fostering interaction with the C terminus were refractory to cyclin D1 action, indicating that the ability of cyclin D1 to modulate AR amino-carboxy terminal interactions is specific to 23FxxLF27. Deletion of the N-terminal cyclin D1 binding site severely compromised AR activity (due to loss of FxxLF) but unmasked a repressor action through interaction with the AR C terminus. In summary, these data reveal novel, unexpected mechanisms of cyclin D1 activity and demonstrate that this function of cyclin D1 is critical for AR modulation.
Burd
C J
CJ
Department of Cell Biology, University of Cincinnati College of Medicine, P.O. Box 670521, 3125 Eden Avenue, Cincinnati, Ohio 45267-0521, USA.
Petre
C E
CE
Moghadam
H
H
Wilson
E M
EM
Knudsen
K E
KE
D000230:Adenocarcinoma / Q000473:pathology; D020816:Amino Acid Motifs; D001665:Binding Sites; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
D011944:Receptors, Androgen; D019938:Cyclin D1