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 NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Burd, C. J. Articles by Knudsen, K. E. Search for Related Content PubMed PubMed Citation Articles by Burd, C. J. Articles by Knudsen, K. E.

Cyclin D1 Binding to the Androgen Receptor (AR) NH₂-Terminal Domain Inhibits Activation Function 2 Association and Reveals Dual Roles for AR Corepression

Department of Cell Biology (C.J.B., C.E.P., H.M., K.E.K.) and Center for Environmental Genetics (K.E.K.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521; and Laboratories of Reproductive Biology (E.M.W.) and the Department of Pediatrics and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7500

Address all correspondence and requests for reprints to: Karen E. Knudsen, Department of Cell Biology, University of Cincinnati College of Medicine, P.O. Box 670521, 3125 Eden Avenue, Cincinnati, Ohio 45267-0521. E-mail: Karen.Knudsen{at}uc.edu.

The androgen receptor (AR) is a member of the nuclear receptor superfamily, the activity of which is critical for the development and progression of prostate cancer. We and others have previously demonstrated that cyclin D1 is a potent corepressor of the AR. Although cyclin D1 is suspected to recruit histone deacetylases to the AR complex, previous studies have demonstrated that this activity alone is insufficient for cyclin D1 function. Here, we uncover a novel, secondary means of cyclin D1-mediated repression, through modulation of AR amino-carboxy terminal interactions. We show that cyclin D1 predominantly binds the N-terminal domain of the AR, dependent on the AR ²³FxxLF²⁷ motif. Through this motif, cyclin D1 abrogates the ability of the AR N-terminal domain to interact with the C terminus. Secondary amino-terminal domain sites capable of fostering interaction with the C terminus were refractory to cyclin D1 action, indicating that the ability of cyclin D1 to modulate AR amino-carboxy terminal interactions is specific to ²³FxxLF²⁷. Deletion of the N-terminal cyclin D1 binding site severely compromised AR activity (due to loss of FxxLF) but unmasked a repressor action through interaction with the AR C terminus. In summary, these data reveal novel, unexpected mechanisms of cyclin D1 activity and demonstrate that this function of cyclin D1 is critical for AR modulation.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   p53  |  Cyclin D1  |  GRIP1

Ligands:   Dihydrotestosterone

This article has been cited by other articles:

				G. E Dressing, C. R Hagan, T. P Knutson, A. R Daniel, and C. A Lange Progesterone receptors act as sensors for mitogenic protein kinases in breast cancer models Endocr. Relat. Cancer, June 1, 2009; 16(2): 351 - 361. [Abstract] [Full Text] [PDF]

				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]

				A. E. Rosenblatt and K. L. Burnstein Inhibition of Androgen Receptor Transcriptional Activity as a Novel Mechanism of Action of Arsenic Mol. Endocrinol., March 1, 2009; 23(3): 412 - 421. [Abstract] [Full Text] [PDF]

				M. M. Centenera, J. M. Harris, W. D. Tilley, and L. M. Butler Minireview: The Contribution of Different Androgen Receptor Domains to Receptor Dimerization and Signaling Mol. Endocrinol., November 1, 2008; 22(11): 2373 - 2382. [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]

				H. Zong, Y. Chi, Y. Wang, Y. Yang, L. Zhang, H. Chen, J. Jiang, Z. Li, Y. Hong, H. Wang, et al. Cyclin D3/CDK11p58 Complex Is Involved in the Repression of Androgen Receptor Mol. Cell. Biol., October 15, 2007; 27(20): 7125 - 7142. [Abstract] [Full Text] [PDF]

				X. Huang, B. Jiao, C. K. Fung, Y. Zhang, W. K K Ho, C. B. Chan, H. Lin, D. Wang, and C. H K Cheng The presence of two distinct prolactin receptors in seabream with different tissue distribution patterns, signal transduction pathways and regulation of gene expression by steroid hormones J. Endocrinol., August 1, 2007; 194(2): 373 - 392. [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]

				S. Carascossa, J. Gobinet, V. Georget, A. Lucas, E. Badia, A. Castet, R. White, J.-C. Nicolas, V. Cavailles, and S. Jalaguier Receptor-Interacting Protein 140 Is a Repressor of the Androgen Receptor Activity Mol. Endocrinol., July 1, 2006; 20(7): 1506 - 1518. [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]