A central domain of cyclin D1 mediates nuclear receptor corepressor activity.
Regulation of nuclear receptor activity is the focus of numerous ongoing studies to develop novel therapies for the treatment of hormone-related cancer. Although cyclin D1 functions to control the activity of several nuclear receptors, the region(s) of the protein responsible for such transcriptional comodulation remain poorly defined. Herein, we map the region of cyclin D1 required for binding and repression of the androgen receptor (AR) to a central, exclusively alpha-helical domain. Deletion of this domain disrupted AR binding and corepressor activity. Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3. Strikingly, overexpression of this repressor region attenuates cell cycle progression in prostatic adenocarcinoma cells. The requirement of this domain for nuclear receptor repression was conserved with respect to thyroid hormone receptor beta-1, whereas cyclin D1 activation of the estrogen receptor occurred independently of the central region. Together, these data identify a minimal repression module within cyclin D1 and demonstrate that the coactivator and corepressor functions of cyclin D1 are distinct. In addition, our data suggest that properties of the cyclin D1 central domain could be exploited to develop novel prostate cancer therapeutics.
Petre-Draviam
Christin E
CE
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Williams
Erin B
EB
Burd
Craig J
CJ
Gladden
Andrew
A
Moghadam
Hamed
H
Meller
Jaroslaw
J
Diehl
J Alan
JA
Knudsen
Karen E
KE
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010957:Plasmids; D011471:Prostatic Neoplasms; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000502:physiology*; D017384:Sequence Deletion; D014162:Transfection
D011944:Receptors, Androgen; D019938:Cyclin D1