HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 8, 6511-6519, February 25, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/8/6511    most recent M408972200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hodgson, M. C. Articles by Hollenberg, A. N. Search for Related Content PubMed PubMed Citation Articles by Hodgson, M. C. Articles by Hollenberg, A. N. Social Bookmarking                      What's this?

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^*

Myles C. Hodgson, Inna Astapova, Shinta Cheng, Larissa J. Lee, Manon C. Verhoeven, Eunis Choi, Steven P. Balk, and Anthony N. Hollenberg

From the Divisions of Hematology/Oncology and Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

The androgen receptor (AR) activates target gene expression in the presence of agonist ligands via the recruitment of transcriptional coactivators, but recent work shows that overexpression of the nuclear corepressors NCoR and SMRT attenuates this agonist-mediated AR activation. Here we demonstrate using NCoR siRNA and chromatin immunoprecipitation that endogenous NCoR is recruited to and represses the dihydrotestosterone (DHT)-liganded AR. Furthermore this study shows that NCoR and coactivators compete for AR in the presence of DHT. AR antagonists such as bicalutamide that are currently in use for prostate cancer treatment can also mediate NCoR recruitment, but mifepristone (RU486) at nanomolar concentrations is unique in its ability to markedly enhance the AR-NCoR interaction. The RU486-liganded AR interacted with a C-terminal fragment of NCoR, and this interaction was mediated by the two most C-terminal nuclear receptor interacting domains (RIDs) present in NCoR. Significantly, in addition to the AR ligand binding domain, the AR N terminus was also required for this interaction. Mutagenesis studies demonstrate that the N-terminal surface of the AR-mediating NCoR recruitment was distinct from tau5 and from the FXXLF motif that mediates agonist-induced N-C-terminal interaction. Taken together these data demonstrate that NCoR is a physiological regulator of the AR and reveal a new mechanism for AR antagonism that may be exploited for the development of more potent AR antagonists.

Received for publication, August 5, 2004 , and in revised form, November 23, 2004.

^* This work was supported by Grants DK61047 (to S. P. B.) and DK56123 (to A. N. H.) from the National Institutes of Health, Department of Defense Grant PC040246, the Dana Farber Harvard Cancer Center Prostate SPORE, and the Hershey Family Prostate Cancer Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: sbalk{at}bidmc.harvard.edu. To whom correspondence may be addressed. E-mail: thollenb{at}bidmc.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Tran, S. Ouk, N. J. Clegg, Y. Chen, P. A. Watson, V. Arora, J. Wongvipat, P. M. Smith-Jones, D. Yoo, A. Kwon, et al. Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer Science, May 8, 2009; 324(5928): 787 - 790. [Abstract] [Full Text] [PDF]

				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]

				N. Khan, M. Asim, F. Afaq, M. Abu Zaid, and H. Mukhtar A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice Cancer Res., October 15, 2008; 68(20): 8555 - 8563. [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]

				L.-N. Song and E. P. Gelmann Silencing Mediator for Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Attenuate Transcriptional Activation by the {beta}-Catenin-TCF4 Complex J. Biol. Chem., September 19, 2008; 283(38): 25988 - 25999. [Abstract] [Full Text] [PDF]

				Y. Dai, D. Ngo, J. Jacob, L. W. Forman, and D. V. Faller Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes Carcinogenesis, September 1, 2008; 29(9): 1725 - 1733. [Abstract] [Full Text] [PDF]

				A. Yemelyanov, J. Czwornog, L. Gera, S. Joshi, R. T. Chatterton Jr., and I. Budunova Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells Cancer Res., June 15, 2008; 68(12): 4763 - 4773. [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]

				X. Dong, J. Sweet, J. R. G. Challis, T. Brown, and S. J. Lye Transcriptional Activity of Androgen Receptor Is Modulated by Two RNA Splicing Factors, PSF and p54nrb Mol. Cell. Biol., July 1, 2007; 27(13): 4863 - 4875. [Abstract] [Full Text] [PDF]

				N. Heldring, T. Pawson, D. McDonnell, E. Treuter, J.-A. Gustafsson, and A. C. W. Pike Structural Insights into Corepressor Recognition by Antagonist-bound Estrogen Receptors J. Biol. Chem., April 6, 2007; 282(14): 10449 - 10455. [Abstract] [Full Text] [PDF]

				T. I. Klokk, P. Kurys, C. Elbi, A. K. Nagaich, A. Hendarwanto, T. Slagsvold, C.-Y. Chang, G. L. Hager, and F. Saatcioglu Ligand-Specific Dynamics of the Androgen Receptor at Its Response Element in Living Cells Mol. Cell. Biol., March 1, 2007; 27(5): 1823 - 1843. [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]

				P Singh, A Uzgare, I Litvinov, S R Denmeade, and J T Isaacs Combinatorial androgen receptor targeted therapy for prostate cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 653 - 666. [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]

				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]

				J. M. Blumberg, I. Tzameli, I. Astapova, F. S. Lam, J. S. Flier, and A. N. Hollenberg Complex Role of the Vitamin D Receptor and Its Ligand in Adipogenesis in 3T3-L1 Cells J. Biol. Chem., April 21, 2006; 281(16): 11205 - 11213. [Abstract] [Full Text] [PDF]

				T. Ichijo, A. Voutetakis, A. P. Cotrim, N. Bhattachryya, M. Fujii, G. P. Chrousos, and T. Kino The Smad6-Histone Deacetylase 3 Complex Silences the Transcriptional Activity of the Glucocorticoid Receptor: POTENTIAL CLINICAL IMPLICATIONS J. Biol. Chem., December 23, 2005; 280(51): 42067 - 42077. [Abstract] [Full Text] [PDF]

				H. I. Scher and C. L. Sawyers Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis J. Clin. Oncol., November 10, 2005; 23(32): 8253 - 8261. [Abstract] [Full Text] [PDF]

				Y. Zhang, D. Akinmade, and A. W. Hamburger The ErbB3 binding protein Ebp1 interacts with Sin3A to repress E2F1 and AR-mediated transcription Nucleic Acids Res., October 27, 2005; 33(18): 6024 - 6033. [Abstract] [Full Text] [PDF]

				Y. Zhang, X.-W. Wang, D. Jelovac, T. Nakanishi, M.-h. Yu, D. Akinmade, O. Goloubeva, D. D. Ross, A. Brodie, and A. W. Hamburger The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells PNAS, July 12, 2005; 102(28): 9890 - 9895. [Abstract] [Full Text] [PDF]