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Molecular Biology of the Androgen Receptor

From the Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, 3800 Reservoir Rd NW, Washington, DC.

Address reprint requests to Edward P. Gelmann, MD, Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, 3800 Reservoir Rd NW, Washington, DC 20007-2197; email: gelmanne{at}georgetown.edu

ABSTRACT: Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.

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				C. J. Burd, C. E. Petre, H. Moghadam, E. M. Wilson, and K. E. Knudsen Cyclin D1 Binding to the Androgen Receptor (AR) NH2-Terminal Domain Inhibits Activation Function 2 Association and Reveals Dual Roles for AR Corepression Mol. Endocrinol., March 1, 2005; 19(3): 607 - 620. [Abstract] [Full Text] [PDF]

				C. W. Gregory, Y. E. Whang, W. McCall, X. Fei, Y. Liu, L. A. Ponguta, F. S. French, E. M. Wilson, and H. S. Earp III Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth Clin. Cancer Res., March 1, 2005; 11(5): 1704 - 1712. [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]

				S. Bai, B. He, and E. M. Wilson Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor Function by Modulating the Interdomain Interaction Mol. Cell. Biol., February 15, 2005; 25(4): 1238 - 1257. [Abstract] [Full Text] [PDF]

				C.-S. Yang, M. J. Vitto, S. A. Busby, B. A. Garcia, C. T. Kesler, D. Gioeli, J. Shabanowitz, D. F. Hunt, K. Rundell, D. L. Brautigan, et al. Simian Virus 40 Small t Antigen Mediates Conformation-Dependent Transfer of Protein Phosphatase 2A onto the Androgen Receptor Mol. Cell. Biol., February 15, 2005; 25(4): 1298 - 1308. [Abstract] [Full Text] [PDF]

				H. L. Parnes, I. M. Thompson, and L. G. Ford Prevention of Hormone-Related Cancers: Prostate Cancer J. Clin. Oncol., January 10, 2005; 23(2): 368 - 377. [Abstract] [Full Text] [PDF]

				Z. Salah, M. Maoz, I. Cohen, G. Pizov, D. Pode, M. S. Runge, and R. Bar-Shavit Identification of a novel functional androgen response element within hPar1 promoter: implications to prostate cancer progression FASEB J, January 1, 2005; 19(1): 62 - 72. [Abstract] [Full Text] [PDF]

				D.-Y. Lin, H.-I Fang, A.-H. Ma, Y.-S. Huang, Y.-S. Pu, G. Jenster, H.-J. Kung, and H.-M. Shih Negative Modulation of Androgen Receptor Transcriptional Activity by Daxx Mol. Cell. Biol., December 15, 2004; 24(24): 10529 - 10541. [Abstract] [Full Text] [PDF]

				M. Verras, J. Brown, X. Li, R. Nusse, and Z. Sun Wnt3a Growth Factor Induces Androgen Receptor-Mediated Transcription and Enhances Cell Growth in Human Prostate Cancer Cells Cancer Res., December 15, 2004; 64(24): 8860 - 8866. [Abstract] [Full Text] [PDF]

				G. T G Chang, M. Jhamai, W. M van Weerden, G. Jenster, and A. O Brinkmann The TRPS1 transcription factor: androgenic regulation in prostate cancer and high expression in breast cancer Endocr. Relat. Cancer, December 1, 2004; 11(4): 815 - 822. [Abstract] [Full Text] [PDF]

				C. Keshava, E. C. McCanlies, and A. Weston CYP3A4 Polymorphisms--Potential Risk Factors for Breast and Prostate Cancer: A HuGE Review Am. J. Epidemiol., November 1, 2004; 160(9): 825 - 841. [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]

				J. Cheng, D. Wang, Z. Wang, and E. T. H. Yeh SENP1 Enhances Androgen Receptor-Dependent Transcription through Desumoylation of Histone Deacetylase 1 Mol. Cell. Biol., July 1, 2004; 24(13): 6021 - 6028. [Abstract] [Full Text] [PDF]

				H.-H. Lee, C.-T. Ho, and J.-K. Lin Theaflavin-3,3'-digallate and penta-O-galloyl-{beta}-D-glucose inhibit rat liver microsomal 5{alpha}-reductase activity and the expression of androgen receptor in LNCaP prostate cancer cells Carcinogenesis, July 1, 2004; 25(7): 1109 - 1118. [Abstract] [Full Text] [PDF]

				X. Liao, J. B. Thrasher, J. Holzbeierlein, S. Stanley, and B. Li Glycogen Synthase Kinase-3{beta} Activity Is Required for Androgen-Stimulated Gene Expression in Prostate Cancer Endocrinology, June 1, 2004; 145(6): 2941 - 2949. [Abstract] [Full Text] [PDF]

				P. K. Vayalil, A. Mittal, and S. K. Katiyar Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF{kappa}B Carcinogenesis, June 1, 2004; 25(6): 987 - 995. [Abstract] [Full Text] [PDF]

				M. Littleton-Kearney and P. D. Hurn Testosterone as a Modulator of Vascular Behavior Biol Res Nurs, April 1, 2004; 5(4): 276 - 285. [Abstract] [PDF]

				B. E. Black, M. J. Vitto, D. Gioeli, A. Spencer, N. Afshar, M. R. Conaway, M. J. Weber, and B. M. Paschal Transient, Ligand-Dependent Arrest of the Androgen Receptor in Subnuclear Foci Alters Phosphorylation and Coactivator Interactions Mol. Endocrinol., April 1, 2004; 18(4): 834 - 850. [Abstract] [Full Text] [PDF]

				C. W. Gregory, X. Fei, L. A. Ponguta, B. He, H. M. Bill, F. S. French, and E. M. Wilson Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer J. Biol. Chem., February 20, 2004; 279(8): 7119 - 7130. [Abstract] [Full Text] [PDF]

				M. J. Linja, K. P. Porkka, Z. Kang, K. J. Savinainen, O. A. Janne, T. L. J. Tammela, R. L. Vessella, J. J. Palvimo, and T. Visakorpi Expression of Androgen Receptor Coregulators in Prostate Cancer Clin. Cancer Res., February 1, 2004; 10(3): 1032 - 1040. [Abstract] [Full Text] [PDF]

				J. L. Mohler, C. W. Gregory, O. H. Ford III, D. Kim, C. M. Weaver, P. Petrusz, E. M. Wilson, and F. S. French The Androgen Axis in Recurrent Prostate Cancer Clin. Cancer Res., January 15, 2004; 10(2): 440 - 448. [Abstract] [Full Text] [PDF]

				P. V. Nantermet, J. Xu, Y. Yu, P. Hodor, D. Holder, S. Adamski, M. A. Gentile, D. B. Kimmel, S.-i. Harada, D. Gerhold, et al. Identification of Genetic Pathways Activated by the Androgen Receptor during the Induction of Proliferation in the Ventral Prostate Gland J. Biol. Chem., January 9, 2004; 279(2): 1310 - 1322. [Abstract] [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]