This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petre-Draviam, C. E. Articles by Knudsen, K. E. Search for Related Content PubMed PubMed Citation Articles by Petre-Draviam, C. E. Articles by Knudsen, K. E.

Specificity of Cyclin D1 for Androgen Receptor Regulation¹

Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521

Androgen receptor (AR) activity is required for prostate growth, differentiation, and secretion. Deregulation of AR activity results in inappropriate mitogenic signaling and is thought to contribute both to the initiation and progression of prostate cancers. Cyclin D1 functions as a strong AR corepressor by directly interacting with and inhibiting receptor activity. However, the extent to which cyclin D1 functions to inhibit AR activity under conditions associated with cancer progression has not been determined. We now demonstrate that cyclin D1 action is conserved in multiple tumor cell backgrounds, inhibiting AR-dependent gene activation in breast, bladder, and androgen-independent prostatic adenocarcinoma cell lines. In androgen-dependent prostatic adenocarcinomas, cyclin D1 effectively muted androgen-stimulated target gene expression in a manner analogous to dominant negative ARs. The ability of cyclin D1 to inhibit AR activity was conserved with regard to target promoter, repressing transactivation from mouse mammary tumor virus, probasin, and prostate-specific antigen promoters. Inappropriate, nonligand AR activation, postulated to act through regulation of receptor phosphorylation, was also sensitive to cyclin D1 regulation. Moreover, we show that several phosphorylation site mutants of the AR were equally inhibited by cyclin D1 as compared with the wild-type receptor. Given these data establishing the potency of cyclin D1-mediated repression, we evaluated the ability of cyclin D1 to inhibit tumor-derived AR alleles and polymorphisms associated with tumor progression and increased prostate cancer risk. We demonstrate that the AR alleles and polymorphisms tested respond completely to cyclin D1 corepressor activity. In addition, activation of a common tumor-derived AR allele by 17ß-estradiol and progesterone was inhibited through ectopic expression of cyclin D1. Taken together, these data establish the potency of cyclin D1 as an AR corepressor and provide support for additional studies examining the efficacy of developing novel prostate cancer therapies for both androgen-dependent and -independent tumors.

This article has been cited by other articles:

				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]

				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]

				B. A. Narayanan, N. K. Narayanan, L. Davis, and D. Nargi RNA interference-mediated cyclooxygenase-2 inhibition prevents prostate cancer cell growth and induces differentiation: modulation of neuronal protein synaptophysin, cyclin D1, and androgen receptor Mol. Cancer Ther., May 1, 2006; 5(5): 1117 - 1125. [Abstract] [Full Text] [PDF]

				C. J. Burd, C. E. Petre, L. M. Morey, Y. Wang, M. P. Revelo, C. A. Haiman, S. Lu, C. M. Fenoglio-Preiser, J. Li, E. S. Knudsen, et al. Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation PNAS, February 14, 2006; 103(7): 2190 - 2195. [Abstract] [Full Text] [PDF]

				D. J. Mulholland, S. Dedhar, G. A. Coetzee, and C. C. Nelson Interaction of Nuclear Receptors with the Wnt/{beta}-Catenin/Tcf Signaling Axis: Wnt You Like to Know? Endocr. Rev., December 1, 2005; 26(7): 898 - 915. [Abstract] [Full Text] [PDF]

				Z Culig, H Steiner, G Bartsch, and A Hobisch Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 229 - 244. [Abstract] [Full Text] [PDF]

				R. Kumar, A. E. Gururaj, R. K. Vadlamudi, and S. K. Rayala The Clinical Relevance of Steroid Hormone Receptor Corepressors Clin. Cancer Res., April 15, 2005; 11(8): 2822 - 2831. [Abstract] [Full Text] [PDF]

				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]

				M. Fu, C. Wang, Z. Li, T. Sakamaki, and R. G. Pestell Minireview: Cyclin D1: Normal and Abnormal Functions Endocrinology, December 1, 2004; 145(12): 5439 - 5447. [Abstract] [Full Text] [PDF]

				G. M. Carbone, S. Napoli, A. Valentini, F. Cavalli, D. K. Watson, and C. V. Catapano Triplex DNA-mediated downregulation of Ets2 expression results in growth inhibition and apoptosis in human prostate cancer cells Nucleic Acids Res., August 16, 2004; 32(14): 4358 - 4367. [Abstract] [Full Text] [PDF]