This Article Full Text Full Text (PDF) All Versions of this Article: 17/8/1484    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart 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 NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gao, N. Articles by Matusik, R. J. Search for Related Content PubMed PubMed Citation Articles by Gao, N. Articles by Matusik, R. J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Genetics Home Reference

The Role of Hepatocyte Nuclear Factor-3 (Forkhead Box A1) and Androgen Receptor in Transcriptional Regulation of Prostatic Genes

Department of Cell and Developmental Biology (N.G., J.Z., R.J.M.), Vanderbilt University Medical Center; Department of Urologic Surgery (N.G., J.Z., T.C.C., J.M., Y.W., R.J., A.G., R.J.M.), and the Vanderbilt Prostate Cancer Center, Vanderbilt University; Department of Cancer Biology (T.C.C., J.M., Y.W., R.J., A.G., R.J.M.), and the Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232; and The Prostate Centre at Vancouver General Hospital (M.A.R., P.S.R.), Vancouver, British Columbia V6H 3Z6, Canada

Address all correspondence and requests for reprints to: Robert J. Matusik, Ph.D., Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232. E-mail: Robert.matusik{at}vanderbilt.edu.

Androgens and mesenchymal factors are essential extracellular signals for the development as well as the functional activity of the prostate epithelium. Little is known of the intraepithelial determinants that are involved in prostatic differentiation. Here we found that hepatocyte nuclear factor-3 (HNF-3), an endoderm developmental factor, is essential for androgen receptor (AR)-mediated prostatic gene activation. Two HNF-3 cis-regulatory elements were identified in the rat probasin (PB) gene promoter, each immediately adjacent to an androgen response element. Remarkably, similar organization of HNF-3 and AR binding sites was observed in the prostate-specific antigen (PSA) gene core enhancer, suggesting a common functional mechanism. Mutations that disrupt these HNF-3 motifs significantly abolished the maximal androgen induction of PB and PSA activities. Overexpressing a mutant HNF-3 deleted in the C-terminal region inhibited the androgen-induced promoter activity in LNCaP cells where endogenous HNF-3 is expressed. Chromatin immunoprecipitation revealed in vivo that the occupancy of HNF-3 on PSA enhancer can occur in an androgen-depleted condition, and before the recruitment of ligand-bound AR. A physical interaction of HNF-3 and AR was detected through immunoprecipitation and confirmed by glutathione-S-transferase pull-down. This interaction is directly mediated through the DNA-binding domain/hinge region of AR and the forkhead domain of HNF-3. In addition, strong HNF-3 expression, but not HNF-3ß or HNF-3, is detected in both human and mouse prostatic epithelial cells where markers (PSA and PB) of differentiation are expressed. Taken together, these data support a model in which regulatory cues from the cell lineage and the extracellular environment coordinately establish the prostatic differentiated response.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   Dihydrotestosterone  |  R1881

This article has been cited by other articles:

				R. J. Jin, Y. Lho, Y. Wang, M. Ao, M. P. Revelo, S. W. Hayward, M. L. Wills, S. K. Logan, P. Zhang, and R. J. Matusik Down-regulation of p57Kip2 Induces Prostate Cancer in the Mouse Cancer Res., May 15, 2008; 68(10): 3601 - 3608. [Abstract] [Full Text] [PDF]

				H. V. Heemers and D. J. Tindall Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex Endocr. Rev., December 1, 2007; 28(7): 778 - 808. [Abstract] [Full Text] [PDF]

				T. Reiner, A. de las Pozas, R. Parrondo, and C. Perez-Stable Progression of Prostate Cancer from a Subset of p63-Positive Basal Epithelial Cells in FG/Tag Transgenic Mice Mol. Cancer Res., November 1, 2007; 5(11): 1171 - 1179. [Abstract] [Full Text] [PDF]

				A. L. M. Ferri, W. Lin, Y. E. Mavromatakis, J. C. Wang, H. Sasaki, J. A. Whitsett, and S.-L. Ang Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner Development, August 1, 2007; 134(15): 2761 - 2769. [Abstract] [Full Text] [PDF]

				X. Yu, K. Suzuki, Y. Wang, A. Gupta, R. Jin, M.-C. Orgebin-Crist, and R. Matusik The Role of Forkhead Box A2 to Restrict Androgen-Regulated Gene Expression of Lipocalin 5 in the Mouse Epididymis Mol. Endocrinol., October 1, 2006; 20(10): 2418 - 2431. [Abstract] [Full Text] [PDF]

				R. Werner, P.-M. Holterhus, G. Binder, H.-P. Schwarz, M. Morlot, D. Struve, C. Marschke, and O. Hiort The A645D Mutation in the Hinge Region of the Human Androgen Receptor (AR) Gene Modulates AR Activity, Depending on the Context of the Polymorphic Glutamine and Glycine Repeats J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3515 - 3520. [Abstract] [Full Text] [PDF]

				J. S. Carroll and M. Brown Estrogen Receptor Target Gene: An Evolving Concept Mol. Endocrinol., August 1, 2006; 20(8): 1707 - 1714. [Abstract] [Full Text] [PDF]

				M. A. Albertelli, A. Scheller, M. Brogley, and D. M. Robins Replacing the Mouse Androgen Receptor with Human Alleles Demonstrates Glutamine Tract Length-Dependent Effects on Physiology and Tumorigenesis in Mice Mol. Endocrinol., June 1, 2006; 20(6): 1248 - 1260. [Abstract] [Full Text] [PDF]

				N. Gao, K. Ishii, J. Mirosevich, S. Kuwajima, S. R. Oppenheimer, R. L. Roberts, M. Jiang, X. Yu, S. B. Shappell, R. M. Caprioli, et al. Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation Development, August 1, 2005; 132(15): 3431 - 3443. [Abstract] [Full Text] [PDF]

				K. V. Desai, A. M. Michalowska, P. Kondaiah, J. M. Ward, J. H. Shih, and J. E. Green Gene Expression Profiling Identifies a Unique Androgen-Mediated Inflammatory/Immune Signature and a PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10)-Mediated Apoptotic Response Specific to the Rat Ventral Prostate Mol. Endocrinol., December 1, 2004; 18(12): 2895 - 2907. [Abstract] [Full Text] [PDF]

				S. M. Brugger, A. E. Merrill, J. Torres-Vazquez, N. Wu, M.-C. Ting, J. Y.-M. Cho, S. L. Dobias, S. E. Yi, K. Lyons, J. R. Bell, et al. A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and Drosophila embryos Development, October 15, 2004; 131(20): 5153 - 5165. [Abstract] [Full Text] [PDF]

				J. Zhang, N. Gao, S. Kasper, K. Reid, C. Nelson, and R. J. Matusik An Androgen-Dependent Upstream Enhancer Is Essential for High Levels of Probasin Gene Expression Endocrinology, January 1, 2004; 145(1): 134 - 148. [Abstract] [Full Text] [PDF]