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 Haelens, A. Articles by Claessens, F. Search for Related Content PubMed PubMed Citation Articles by Haelens, A. Articles by Claessens, F.

The Hinge Region Regulates DNA Binding, Nuclear Translocation, and Transactivation of the Androgen Receptor

Molecular Endocrinology Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Campus Gasthuisberg, University of Leuven, Leuven, Belgium

Requests for reprints: Frank Claessens, Campus GHB O/N Room 901, Herestraat 49, 3000 Leuven, Belgium. Phone: 32-16-330253; Fax: 32-16-345995; E-mail: frank.claessens{at}med.kuleuven.be.

The androgen receptor (AR) encoding gene can undergo mutations during the development and treatment of prostate cancer. Even in hormone-independent stages, mutations in the receptor paradoxically seem to result in an increased AR function. Two such point mutations have been described in the part of the AR involved in DNA binding and nuclear translocation, namely the hinge region. Despite a decreased nuclear translocation, these mutant ARs display increased transactivating potencies. Through detailed analysis of the hinge region, we found that deletion of residues 629 to 636 resulted in a stronger androgen response on different reporters, although this mutant displays an extremely low in vitro affinity for androgen response elements. This superactivity is independent of nuclear localization and can be inhibited by antiandrogens. Surprisingly, the AR activation functions, AF1 and AF2, are not dramatically affected when the inhibitory region (629-RKLKKLGN-636) is deleted, although cotransfected p160 coactivator TIF2 had a stronger potentiating effect in the absence of this motif. The ligand-dependent interaction between the amino-terminal domain and the ligand-binding domain (N/C interaction) plays an important role in transactivation by the AR. We found that this interaction is strongly enhanced by deletion of the inhibitory region. In conclusion, the description of prostate cancer mutations has led to the discovery of a complex role of the hinge region in nuclear localization, DNA binding, coactivator recruitment, and N/C interaction of the AR. [Cancer Res 2007;67(9):4514–23]

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]

				S. Kaikkonen, T. Jaaskelainen, U. Karvonen, M. M. Rytinki, H. Makkonen, D. Gioeli, B. M. Paschal, and J. J. Palvimo SUMO-Specific Protease 1 (SENP1) Reverses the Hormone-Augmented SUMOylation of Androgen Receptor and Modulates Gene Responses in Prostate Cancer Cells Mol. Endocrinol., March 1, 2009; 23(3): 292 - 307. [Abstract] [Full Text] [PDF]

				A. Deeb, J. Jaaskelainen, M. Dattani, H. C. Whitaker, C. Costigan, and I. A. Hughes A Novel Mutation in the Human Androgen Receptor Suggests a Regulatory Role for the Hinge Region in Amino-Terminal and Carboxy-Terminal Interactions J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3691 - 3696. [Abstract] [Full Text] [PDF]

				K. A. Link, S. Balasubramaniam, A. Sharma, C. E.S. Comstock, S. Godoy-Tundidor, N. Powers, K. H. Cao, A. Haelens, F. Claessens, M. P. Revelo, et al. Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity Cancer Res., June 15, 2008; 68(12): 4551 - 4558. [Abstract] [Full Text] [PDF]

				M. L. Cutress, H. C. Whitaker, I. G. Mills, M. Stewart, and D. E. Neal Structural basis for the nuclear import of the human androgen receptor J. Cell Sci., April 1, 2008; 121(7): 957 - 968. [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]