This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheng, S. Articles by Balk, S. P. Search for Related Content PubMed PubMed Citation Articles by Cheng, S. Articles by Balk, S. P.

Inhibition of the Dihydrotestosterone-Activated Androgen Receptor by Nuclear Receptor Corepressor

Cancer Biology Program, Division of Hematology-Oncology (S.C., S.R.L., S.P.B.) and Thyroid Unit, Division of Endocrinology (S.B., A.N.H.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Anthony N. Hollenberg, Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. E-mail: thollenb{at}caregroup.harvard.edu; or Steven P. Balk, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215; E-mail: sbalk{at}caregroup.harvard.edu.

Nuclear receptor corepressor (NCoR) mediates transcriptional repression by unliganded nuclear receptors and certain steroid hormone receptors (SHRs) bound to nonphysiological antagonists, but has not been found to regulate SHRs bound to their natural ligands. This report demonstrates that NCoR interacts directly with the androgen receptor (AR) and represses dihydrotestosterone-stimulated AR transcriptional activity. The NCoR C terminus, containing the receptor interacting domains, was necessary for repression, which was ablated by mutations in the corepressor nuclear receptor (CoRNR) boxes. In contrast, the NCoR N terminus, containing domains that can recruit histone deacetylases, was not necessary for repression. Binding studies in vitro with a series of glutathione-S-transferase-NCoR and -AR fusion proteins demonstrated a direct interaction that was similarly dependent upon the NCoR corepressor nuclear receptor boxes and AR ligand binding domain and was independent of ligand and helix 12 in the AR ligand binding domain. This NCoR-AR interaction was further demonstrated in mammalian two-hybrid assays and by coimmunoprecipitation of the endogenous proteins from a prostate cancer cell line. Finally, AR transcriptional activity could be enhanced in vivo by sequestration of endogenous NCoR with unliganded thyroid hormone receptor. These results demonstrate that AR, in contrast to other SHRs, is regulated by NCoR and suggest the possibility of developing selective AR modulators that enhance this interaction.

This article has been cited by other articles:

				K. Wu, S. Katiyar, A. Witkiewicz, A. Li, P. McCue, L.-N. Song, L. Tian, M. Jin, and R. G. Pestell The Cell Fate Determination Factor Dachshund Inhibits Androgen Receptor Signaling and Prostate Cancer Cellular Growth Cancer Res., April 15, 2009; 69(8): 3347 - 3355. [Abstract] [Full Text] [PDF]

				M. C. Hodgson, H. C. Shen, A. N. Hollenberg, and S. P. Balk Structural basis for nuclear receptor corepressor recruitment by antagonist-liganded androgen receptor Mol. Cancer Ther., October 1, 2008; 7(10): 3187 - 3194. [Abstract] [Full Text] [PDF]

				M. L. Cutress, H. C. Whitaker, I. G. Mills, M. Stewart, and D. E. Neal Structural basis for the nuclear import of the human androgen receptor J. Cell Sci., April 1, 2008; 121(7): 957 - 968. [Abstract] [Full Text] [PDF]

				M. C. Hodgson, I. Astapova, A. N. Hollenberg, and S. P. Balk Activity of Androgen Receptor Antagonist Bicalutamide in Prostate Cancer Cells Is Independent of NCoR and SMRT Corepressors Cancer Res., September 1, 2007; 67(17): 8388 - 8395. [Abstract] [Full Text] [PDF]

				T. J. Peterson, S. Karmakar, M. C. Pace, T. Gao, and C. L. Smith The Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) Corepressor Is Required for Full Estrogen Receptor {alpha} Transcriptional Activity Mol. Cell. Biol., September 1, 2007; 27(17): 5933 - 5948. [Abstract] [Full Text] [PDF]

				Y. Dai, D. Ngo, L. W. Forman, D. C. Qin, J. Jacob, and D. V. Faller Sirtuin 1 Is Required for Antagonist-Induced Transcriptional Repression of Androgen-Responsive Genes by the Androgen Receptor Mol. Endocrinol., August 1, 2007; 21(8): 1807 - 1821. [Abstract] [Full Text] [PDF]

				C. J Burd, L. M Morey, and K. E Knudsen Androgen receptor corepressors and prostate cancer Endocr. Relat. Cancer, December 1, 2006; 13(4): 979 - 994. [Abstract] [Full Text] [PDF]

				I. R. Logan, L. Gaughan, S. R. C. McCracken, V. Sapountzi, H. Y. Leung, and C. N. Robson Human PIRH2 Enhances Androgen Receptor Signaling through Inhibition of Histone Deacetylase 1 and Is Overexpressed in Prostate Cancer. Mol. Cell. Biol., September 1, 2006; 26(17): 6502 - 6510. [Abstract] [Full Text] [PDF]

				Y. Wu, H. Kawate, K. Ohnaka, H. Nawata, and R. Takayanagi Nuclear Compartmentalization of N-CoR and Its Interactions with Steroid Receptors. Mol. Cell. Biol., September 1, 2006; 26(17): 6633 - 6655. [Abstract] [Full Text] [PDF]

				S. Carascossa, J. Gobinet, V. Georget, A. Lucas, E. Badia, A. Castet, R. White, J.-C. Nicolas, V. Cavailles, and S. Jalaguier Receptor-Interacting Protein 140 Is a Repressor of the Androgen Receptor Activity Mol. Endocrinol., July 1, 2006; 20(7): 1506 - 1518. [Abstract] [Full Text] [PDF]

				H.-G. Yoon and J. Wong The Corepressors Silencing Mediator of Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Are Involved in Agonist- and Antagonist-Regulated Transcription by Androgen Receptor Mol. Endocrinol., May 1, 2006; 20(5): 1048 - 1060. [Abstract] [Full Text] [PDF]

				D. Wang and S. S. Simons Jr. Corepressor Binding to Progesterone and Glucocorticoid Receptors Involves the Activation Function-1 Domain and Is Inhibited by Molybdate Mol. Endocrinol., June 1, 2005; 19(6): 1483 - 1500. [Abstract] [Full Text] [PDF]

				M. C. Hodgson, I. Astapova, S. Cheng, L. J. Lee, M. C. Verhoeven, E. Choi, S. P. Balk, and A. N. Hollenberg The Androgen Receptor Recruits Nuclear Receptor CoRepressor (N-CoR) in the Presence of Mifepristone via Its N and C Termini Revealing a Novel Molecular Mechanism for Androgen Receptor Antagonists J. Biol. Chem., February 25, 2005; 280(8): 6511 - 6519. [Abstract] [Full Text] [PDF]

				C. Jung, R.-S. Kim, H.-J. Zhang, S.-J. Lee, and M.-H. Jeng HOXB13 Induces Growth Suppression of Prostate Cancer Cells as a Repressor of Hormone-Activated Androgen Receptor Signaling Cancer Res., December 15, 2004; 64(24): 9185 - 9192. [Abstract] [Full Text] [PDF]

				Z. Kang, O. A. Janne, and J. J. Palvimo Coregulator Recruitment and Histone Modifications in Transcriptional Regulation by the Androgen Receptor Mol. Endocrinol., November 1, 2004; 18(11): 2633 - 2648. [Abstract] [Full Text] [PDF]

				D. Masiello, S.-Y. Chen, Y. Xu, M. C. Verhoeven, E. Choi, A. N. Hollenberg, and S. P. Balk Recruitment of {beta}-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells Mol. Endocrinol., October 1, 2004; 18(10): 2388 - 2401. [Abstract] [Full Text] [PDF]

				H. I Scher, G. Buchanan, W. Gerald, L. M Butler, and W. D Tilley Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer Endocr. Relat. Cancer, September 1, 2004; 11(3): 459 - 476. [Abstract] [Full Text] [PDF]

				M. Powzaniuk, S. McElwee-Witmer, R. L. Vogel, T. Hayami, S. J. Rutledge, F. Chen, S.-i. Harada, A. Schmidt, G. A. Rodan, L. P. Freedman, et al. The LATS2/KPM Tumor Suppressor Is a Negative Regulator of the Androgen Receptor Mol. Endocrinol., August 1, 2004; 18(8): 2011 - 2023. [Abstract] [Full Text] [PDF]

				Q. Wang, J. A. Blackford Jr., L.-N. Song, Y. Huang, S. Cho, and S. S. Simons Jr. Equilibrium Interactions of Corepressors and Coactivators with Agonist and Antagonist Complexes of Glucocorticoid Receptors Mol. Endocrinol., June 1, 2004; 18(6): 1376 - 1395. [Abstract] [Full Text] [PDF]

				M. Rahman, H. Miyamoto, and C. Chang Androgen Receptor Coregulators in Prostate Cancer: Mechanisms and Clinical Implications Clin. Cancer Res., April 1, 2004; 10(7): 2208 - 2219. [Full Text] [PDF]

				L.-N. Song, M. Coghlan, and E. P. Gelmann Antiandrogen Effects of Mifepristone on Coactivator and Corepressor Interactions with the Androgen Receptor Mol. Endocrinol., January 1, 2004; 18(1): 70 - 85. [Abstract] [Full Text] [PDF]

				I. U. Agoulnik, W. C. Krause, W. E. Bingman III, H. T. Rahman, M. Amrikachi, G. E. Ayala, and N. L. Weigel Repressors of Androgen and Progesterone Receptor Action J. Biol. Chem., August 15, 2003; 278(33): 31136 - 31148. [Abstract] [Full Text] [PDF]

				L. Jia, J. Kim, H. Shen, P. E. Clark, W. D. Tilley, and G. A. Coetzee Androgen Receptor Activity at the Prostate Specific Antigen Locus: Steroidal and Non-Steroidal Mechanisms Mol. Cancer Res., March 1, 2003; 1(5): 385 - 392. [Abstract] [Full Text] [PDF]