Molecular Endocrinology, Vol 9, 1017-1028, Copyright © 1995 by Endocrine Society

ARTICLES

Androgen receptor-mediated transcriptional regulation in the absence of direct interaction with a specific DNA element

PJ Kallio, H Poukka, A Moilanen, OA Janne and JJ Palvimo
Department of Physiology, University of Helsinki, Finland.

Androgen receptor (AR) brings about a ligand-dependent inhibition of low-affinity neurotrophin receptor (p75) promoter constructs in cultured cells, with the greatest inhibition being achieved with a reporter gene containing 1050 nucleotides (nt) of the promoter. The receptor domain critical for trans-repression localizes to the same region (amino acids 147-296) as that mandatory for transactivation. In contrast to trans-activation, AR does not interact directly with specific DNA elements to elicit trans-repression of p75 promoter constructs, although an intact DNA-binding domain of the receptor is required for both actions. In a search for interacting partners, both extensively purified full-length AR and AR-DNA binding domain were found to inhibit c-Jun/AP-1 site interaction without themselves binding to the AP-1 element. Prior binding of c-Jun to the AP-1 element protected the complex from the receptor's interference. Repression was not mutual, as c-Jun did not inhibit AR-androgen response element interaction or trans-activation through an androgen response element- containing promoter. The 1050-nt-long p75 promoter sequence does not contain an AP-1 element; an AP-1-like site in the vector backbone mediates the trans-repression by the AR in recipient cells. Intriguingly, an AR form with a large N-terminal deletion (the delta 46- 408 mutant) behaved as a transcriptional activator of the p75 promoter through a mechanism that was also independent of specific DNA binding. Collectively, these data indicate that, in a proper context, AR is able to elicit both transrepression and trans-activation without interacting directly with specific DNA elements. Sequences responsible for the down- regulation of p75 mRNA by androgens in vivo are, however, not located in the proximal 1050 nt of the p75 promoter.

This article has been cited by other articles:

				W. Zhao, J. Pan, X. Wang, Y. Wu, W. A. Bauman, and C. P. Cardozo Expression of the Muscle Atrophy Factor Muscle Atrophy F-Box Is Suppressed by Testosterone Endocrinology, November 1, 2008; 149(11): 5449 - 5460. [Abstract] [Full Text] [PDF]

				U. Moehren, M. Papaioannou, C. A. Reeb, A. Grasselli, S. Nanni, M. Asim, D. Roell, I. Prade, A. Farsetti, and A. Baniahmad Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development FASEB J, April 1, 2008; 22(4): 1258 - 1267. [Abstract] [Full Text] [PDF]

				V. G. Thackray and P. L. Mellon Synergistic Induction of Follicle-Stimulating Hormone {beta}-Subunit Gene Expression by Gonadal Steroid Hormone Receptors and Smad Proteins Endocrinology, March 1, 2008; 149(3): 1091 - 1102. [Abstract] [Full Text] [PDF]

				V. G. Thackray, S. M. McGillivray, and P. L. Mellon Androgens, Progestins, and Glucocorticoids Induce Follicle-Stimulating Hormone {beta}-Subunit Gene Expression at the Level of the Gonadotrope Mol. Endocrinol., September 1, 2006; 20(9): 2062 - 2079. [Abstract] [Full Text] [PDF]

				G. Sathya, C.-y. Chang, D. Kazmin, C. E. Cook, and D. P. McDonnell Pharmacological Uncoupling of Androgen Receptor-mediated Prostate Cancer Cell Proliferation and Prostate-specific Antigen Secretion Cancer Res., November 15, 2003; 63(22): 8029 - 8036. [Abstract] [Full Text] [PDF]

				K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]

				P. Li, H. Lee, S. Guo, T. G. Unterman, G. Jenster, and W. Bai AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR Mol. Cell. Biol., January 1, 2003; 23(1): 104 - 118. [Abstract] [Full Text]

				N. Kotaja, U. Karvonen, O. A. Janne, and J. J. Palvimo PIAS Proteins Modulate Transcription Factors by Functioning as SUMO-1 Ligases Mol. Cell. Biol., July 15, 2002; 22(14): 5222 - 5234. [Abstract] [Full Text] [PDF]

				N. Rouleau, A. Domans'kyi, M. Reeben, A.-M. Moilanen, K. Havas, Z. Kang, T. Owen-Hughes, J. J. Palvimo, and O. A. Janne Novel ATPase of SNF2-like Protein Family Interacts with Androgen Receptor and Modulates Androgen-dependent Transcription Mol. Biol. Cell, June 1, 2002; 13(6): 2106 - 2119. [Abstract] [Full Text] [PDF]

				M. Fu, C. Wang, J. Wang, X. Zhang, T. Sakamaki, Y. G. Yeung, C. Chang, T. Hopp, S. A. W. Fuqua, E. Jaffray, et al. Androgen Receptor Acetylation Governs trans Activation and MEKK1-Induced Apoptosis without Affecting In Vitro Sumoylation and trans-Repression Function Mol. Cell. Biol., May 15, 2002; 22(10): 3373 - 3388. [Abstract] [Full Text] [PDF]

				N. Kotaja, M. Vihinen, J. J. Palvimo, and O. A. Janne Androgen Receptor-interacting Protein 3 and Other PIAS Proteins Cooperate with Glucocorticoid Receptor-interacting Protein 1 in Steroid Receptor-dependent Signaling J. Biol. Chem., May 10, 2002; 277(20): 17781 - 17788. [Abstract] [Full Text] [PDF]

				J. S. Jorgensen and J. H. Nilson AR Suppresses Transcription of the {alpha} Glycoprotein Hormone Subunit Gene Through Protein-Protein Interactions with cJun and Activation Transcription Factor 2 Mol. Endocrinol., September 1, 2001; 15(9): 1496 - 1504. [Abstract] [Full Text] [PDF]

				J. S. Jorgensen and J. H. Nilson AR Suppresses Transcription of the LH{beta} Subunit by Interacting with Steroidogenic Factor-1 Mol. Endocrinol., September 1, 2001; 15(9): 1505 - 1516. [Abstract] [Full Text] [PDF]

				J. Thompson, F. Saatcioglu, O. A. Janne, and J. J. Palvimo Disrupted Amino- and Carboxyl-Terminal Interactions of the Androgen Receptor Are Linked to Androgen Insensitivity Mol. Endocrinol., June 1, 2001; 15(6): 923 - 935. [Abstract] [Full Text] [PDF]

				J. M. Grad, L. S. Lyons, D. M. Robins, and K. L. Burnstein The Androgen Receptor (AR) Amino-Terminus Imposes Androgen-Specific Regulation of AR Gene Expression via an Exonic Enhancer Endocrinology, March 1, 2001; 142(3): 1107 - 1116. [Abstract] [Full Text] [PDF]

				H.-Y. Kang, H.-K. Lin, Y.-C. Hu, S. Yeh, K.-E. Huang, and C. Chang From transforming growth factor-beta signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells PNAS, March 1, 2001; (2001) 61305498. [Abstract] [Full Text]

				N. Kotaja, S. Aittomäki, O. Silvennoinen, J. J. Palvimo, and O. A. Jänne ARIP3 (Androgen Receptor-Interacting Protein 3) and Other PIAS (Protein Inhibitor of Activated STAT) Proteins Differ in Their Ability to Modulate Steroid Receptor-Dependent Transcriptional Activation Mol. Endocrinol., December 1, 2000; 14(12): 1986 - 2000. [Abstract] [Full Text]

				H. Poukka, P. Aarnisalo, H. Santti, O. A. Janne, and J. J. Palvimo Coregulator Small Nuclear RING Finger Protein (SNURF) Enhances Sp1- and Steroid Receptor-mediated Transcription by Different Mechanisms J. Biol. Chem., January 7, 2000; 275(1): 571 - 579. [Abstract] [Full Text] [PDF]

				V. Boonyaratanakornkit, D. D. Strong, S. Mohan, D. J. Baylink, C. A. Beck, and T. A. Linkhart Progesterone Stimulation of Human Insulin-like Growth Factor-binding Protein-5 Gene Transcription in Human Osteoblasts Is Mediated by a CACCC Sequence in the Proximal Promoter J. Biol. Chem., September 10, 1999; 274(37): 26431 - 26438. [Abstract] [Full Text] [PDF]

				L. I. McKay and J. A. Cidlowski Molecular Control of Immune/Inflammatory Responses: Interactions Between Nuclear Factor-{kappa}B and Steroid Receptor-Signaling Pathways Endocr. Rev., August 1, 1999; 20(4): 435 - 459. [Abstract] [Full Text] [PDF]

				M. O. Ripple, W. F. Henry, S. R. Schwarze, G. Wilding, and R. Weindruch Effect of Antioxidants on Androgen-Induced AP-1 and NF-{kappa}B DNA-Binding Activity in Prostate Carcinoma Cells J Natl Cancer Inst, July 21, 1999; 91(14): 1227 - 1232. [Abstract] [Full Text] [PDF]

				H. Poukka, P. Aarnisalo, U. Karvonen, J. J. Palvimo, and O. A. Janne Ubc9 Interacts with the Androgen Receptor and Activates Receptor-dependent Transcription J. Biol. Chem., July 2, 1999; 274(27): 19441 - 19446. [Abstract] [Full Text] [PDF]

				P. Aarnisalo, H. Santti, H. Poukka, J. J. Palvimo, and O. A. Jänne Transcription Activating and Repressing Functions of the Androgen Receptor Are Differentially Influenced by Mutations in the Deoxyribonucleic Acid-Binding Domain Endocrinology, July 1, 1999; 140(7): 3097 - 3105. [Abstract] [Full Text]

				A.-M. Moilanen, U. Karvonen, H. Poukka, W. Yan, J. Toppari, O. A. Janne, and J. J. Palvimo A Testis-specific Androgen Receptor Coregulator That Belongs to a Novel Family of Nuclear Proteins J. Biol. Chem., February 5, 1999; 274(6): 3700 - 3704. [Abstract] [Full Text] [PDF]

				J.-M. Lobaccaro, N. Poujol, B. Térouanne, V. Georget, S. Fabre, S. Lumbroso, and C. Sultan Transcriptional Interferences between Normal or Mutant Androgen Receptors and the Activator Protein 1--Dissection of the Androgen Receptor Functional Domains Endocrinology, January 1, 1999; 140(1): 350 - 357. [Abstract] [Full Text]

				P.-Z. Tang, C. H. Tsai-Morris, and M. L. Dufau Regulation of 3{beta}-Hydroxysteroid Dehydrogenase in Gonadotropin-Induced Steroidogenic Desensitization of Leydig Cells Endocrinology, November 1, 1998; 139(11): 4496 - 4505. [Abstract] [Full Text] [PDF]

				A.-M. Moilanen, H. Poukka, U. Karvonen, M. Häkli, O. A. Jänne, and J. J. Palvimo Identification of a Novel RING Finger Protein as a Coregulator in Steroid Receptor-Mediated Gene Transcription Mol. Cell. Biol., September 1, 1998; 18(9): 5128 - 5139. [Abstract] [Full Text]

				A.-M. Moilanen, U. Karvonen, H. Poukka, O. A. Jänne, and J. J. Palvimo Activation of Androgen Receptor Function by a Novel Nuclear Protein Kinase Mol. Biol. Cell, September 1, 1998; 9(9): 2527 - 2543. [Abstract] [Full Text]

				C. S. Song, M. H. Jung, S. C. Kim, T. Hassan, A. K. Roy, and B. Chatterjee Tissue-specific and Androgen-repressible Regulation of the Rat Dehydroepiandrosterone Sulfotransferase Gene Promoter J. Biol. Chem., August 21, 1998; 273(34): 21856 - 21866. [Abstract] [Full Text] [PDF]

				P. Aarnisalo, J. J. Palvimo, and O. A. Janne CREB-binding protein in androgen receptor-mediated signaling PNAS, March 3, 1998; 95(5): 2122 - 2127. [Abstract] [Full Text] [PDF]

				T. Ikonen, J. J. Palvimo, and O. A. Janne Interaction between the Amino- and Carboxyl-terminal Regions of the Rat Androgen Receptor Modulates Transcriptional Activity and Is Influenced by Nuclear Receptor Coactivators J. Biol. Chem., November 21, 1997; 272(47): 29821 - 29828. [Abstract] [Full Text] [PDF]

				L. L. Heckert, E. M. Wilson, and J. H. Nilson Transcriptional Repression of the {alpha}-Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor Mol. Endocrinol., September 1, 1997; 11(10): 1497 - 1506. [Abstract] [Full Text]

				N. Sato, M. D. Sadar, N. Bruchovsky, F. Saatcioglu, P. S. Rennie, S. Sato, P. H. Lange, and M. E. Gleave Androgenic Induction of Prostate-specific Antigen Gene Is Repressed by Protein-Protein Interaction between the Androgen Receptor and AP-1/c-Jun in the Human Prostate Cancer Cell Line LNCaP J. Biol. Chem., July 11, 1997; 272(28): 17485 - 17494. [Abstract] [Full Text] [PDF]

				R. M. Uht, C. M. Anderson, P. Webb, and P. J. Kushner Transcriptional Activities of Estrogen and Glucocorticoid Receptors Are Functionally Integrated at the AP-1 Response Element Endocrinology, July 1, 1997; 138(7): 2900 - 2908. [Abstract] [Full Text] [PDF]

				U. Karvonen, P. J. Kallio, O. A. Janne, and J. J. Palvimo Interaction of Androgen Receptors with Androgen Response Element in Intact Cells. ROLES OF AMINO- AND CARBOXYL-TERMINAL REGIONS AND THE LIGAND J. Biol. Chem., June 20, 1997; 272(25): 15973 - 15979. [Abstract] [Full Text] [PDF]

				S.-y. Chen, J. Wang, G.-q. Yu, W. Liu, and D. Pearce Androgen and Glucocorticoid Receptor Heterodimer Formation. A POSSIBLE MECHANISM FOR MUTUAL INHIBITION OF TRANSCRIPTIONAL ACTIVITY J. Biol. Chem., May 30, 1997; 272(22): 14087 - 14092. [Abstract] [Full Text] [PDF]

				P. M. Yen, Y. Liu, J. J. Palvimo, M. Trifiro, J. Whang, L. Pinsky, O. A. Jänne, and W. W. Chin Mutant and Wild-Type Androgen Receptors Exhibit Cross-Talk on Androgen-, Glucocorticoid-, and Progesterone-Mediated Transcription Mol. Endocrinol., February 1, 1997; 11(2): 162 - 171. [Abstract] [Full Text]

				M. Burgos-Trinidad, G. L. Youngblood, M. R. Maroto, A. Scheller, D. M. Robins, and A. H. Payne Repression of cAMP-Induced Expression of The Mouse P450 17{{alpha}}-Hydroxylase/C17-20 Lyase Gene (Cyp17) by Androgens Mol. Endocrinol., January 1, 1997; 11(1): 87 - 96. [Abstract] [Full Text]

				N. L. Chamberlain, D. C. Whitacre, and R. L. Miesfeld Delineation of Two Distinct Type 1Activation Functions in the Androgen Receptor Amino-terminal Domain J. Biol. Chem., October 25, 1996; 271(43): 26772 - 26778. [Abstract] [Full Text] [PDF]

				E. T. Keller, C. Chang, and W. B. Ershler Inhibition of NFkappa B Activity through Maintenance of Ikappa Balpha Levels Contributes to Dihydrotestosterone-mediated Repression of the Interleukin-6 Promoter J. Biol. Chem., October 18, 1996; 271(42): 26267 - 26275. [Abstract] [Full Text] [PDF]

				J. Schneikert, H. Peterziel, P.-A. Defossez, H. Klocker, Y. d. Launoit, and A. C.B. Cato Androgen Receptor-Ets Protein Interaction Is a Novel Mechanism for Steroid Hormone-mediated Down-modulation of Matrix Metalloproteinase Expression J. Biol. Chem., September 27, 1996; 271(39): 23907 - 23913. [Abstract] [Full Text] [PDF]

				J. J. Palvimo, P. Reinikainen, T. Ikonen, P. J. Kallio, A. Moilanen, and O. A. Janne Mutual Transcriptional Interference between RelA and Androgen Receptor J. Biol. Chem., September 27, 1996; 271(39): 24151 - 24156. [Abstract] [Full Text] [PDF]

				M. Hakli, U. Karvonen, O. A. Janne, and J. J. Palvimo The RING Finger Protein SNURF Is a Bifunctional Protein Possessing DNA Binding Activity J. Biol. Chem., June 22, 2001; 276(26): 23653 - 23660. [Abstract] [Full Text] [PDF]

				H.-Y. Kang, H.-K. Lin, Y.-C. Hu, S. Yeh, K.-E. Huang, and C. Chang From transforming growth factor-beta signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells PNAS, March 13, 2001; 98(6): 3018 - 3023. [Abstract] [Full Text] [PDF]