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 Magee, J. A. Articles by Milbrandt, J. Search for Related Content PubMed PubMed Citation Articles by Magee, J. A. Articles by Milbrandt, J.

Direct, Androgen Receptor-Mediated Regulation of the FKBP5 Gene via a Distal Enhancer Element

Department of Pathology (J.A.M., J.M.), Division of Laboratory Medicine, Department of Biomedical Engineering (L.C.), and Department of Genetics (G.D.S.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Jeffrey Milbrandt, Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: jeff{at}pathbox.wustl.edu.

Androgen signaling via the androgen receptor (AR) transcription factor is crucial to normal prostate homeostasis and prostate tumorigenesis. Current models of AR function are predominantly based on studies of prostate-specific antigen regulation in androgen-responsive cell lines. To expand on these in vitro paradigms, we used the mouse prostate to elucidate the mechanisms through which AR regulates another direct target, FKBP5, in vivo. FKBP5 encodes an immunophilin that has been previously implicated in glucocorticoid and progestin signaling pathways and that likely influences prostate physiology in the presence of androgens. In this work, we show that androgens directly regulate FKBP5 via an interaction between the AR and a distal enhancer located 65 kb downstream of the transcription start site in the fifth intron of the FKBP5 gene. We have found that AR selectively recruits cAMP response element-binding protein to this enhancer. These interactions, in turn, result in chromatin remodeling that affects the enhancer proper but not the FKBP5 locus as a whole. Furthermore, in contrast to prostate-specific antigen-regulatory mechanisms, we show that transactivation of the FKBP5 gene does not rely on a single looping complex to mediate communication between the distal enhancer and proximal promoter. Rather, the distal enhancer complex and basal transcription apparatus communicate indirectly with one another, implicating a regulatory mechanism that has not been previously appreciated for AR target genes.

This article has been cited by other articles:

				E. F. Need, H. I. Scher, A. A. Peters, N. L. Moore, A. Cheong, C. J. Ryan, G. A. Wittert, V. R. Marshall, W. D. Tilley, and G. Buchanan A Novel Androgen Receptor Amino Terminal Region Reveals Two Classes of Amino/Carboxyl Interaction-Deficient Variants with Divergent Capacity to Activate Responsive Sites in Chromatin Endocrinology, June 1, 2009; 150(6): 2674 - 2682. [Abstract] [Full Text] [PDF]

				H. Makkonen, M. Kauhanen, V. Paakinaho, T. Jaaskelainen, and J. J. Palvimo Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers Nucleic Acids Res., May 11, 2009; (2009) gkp352v1. [Abstract] [Full Text] [PDF]

				S. Lee, D.-H. Kim, Y. H. Goo, Y. C. Lee, S.-K. Lee, and J. W. Lee Crucial Roles for Interactions between MLL3/4 and INI1 in Nuclear Receptor Transactivation Mol. Endocrinol., May 1, 2009; 23(5): 610 - 619. [Abstract] [Full Text] [PDF]

				J.-C. Pignon, B. Koopmansch, G. Nolens, L. Delacroix, D. Waltregny, and R. Winkler Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines Cancer Res., April 1, 2009; 69(7): 2941 - 2949. [Abstract] [Full Text] [PDF]

				A. Magklara and C. L. Smith A Composite Intronic Element Directs Dynamic Binding of the Progesterone Receptor and GATA-2 Mol. Endocrinol., January 1, 2009; 23(1): 61 - 73. [Abstract] [Full Text] [PDF]

				C. T. Kesler, D. Gioeli, M. R. Conaway, M. J. Weber, and B. M. Paschal Subcellular Localization Modulates Activation Function 1 Domain Phosphorylation in the Androgen Receptor Mol. Endocrinol., September 1, 2007; 21(9): 2071 - 2084. [Abstract] [Full Text] [PDF]

				A. P. Mogal, R. van der Meer, P. S. Crooke, and S. A. Abdulkadir Haploinsufficient Prostate Tumor Suppression by Nkx3.1: A ROLE FOR CHROMATIN ACCESSIBILITY IN DOSAGE-SENSITIVE GENE REGULATION J. Biol. Chem., August 31, 2007; 282(35): 25790 - 25800. [Abstract] [Full Text] [PDF]

				E. C. Bolton, A. Y. So, C. Chaivorapol, C. M. Haqq, H. Li, and K. R. Yamamoto Cell- and gene-specific regulation of primary target genes by the androgen receptor Genes & Dev., August 15, 2007; 21(16): 2005 - 2017. [Abstract] [Full Text] [PDF]

				N. G. Nickols and P. B. Dervan Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide PNAS, June 19, 2007; 104(25): 10418 - 10423. [Abstract] [Full Text] [PDF]

				W. Yong, Z. Yang, S. Periyasamy, H. Chen, S. Yucel, W. Li, L. Y. Lin, I. M. Wolf, M. J. Cohn, L. S. Baskin, et al. Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology J. Biol. Chem., February 16, 2007; 282(7): 5026 - 5036. [Abstract] [Full Text] [PDF]