This Article Full Text Full Text (PDF) Supplementary Data 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 Dehm, S. M. Articles by Tindall, D. J. Search for Related Content PubMed PubMed Citation Articles by Dehm, S. M. Articles by Tindall, D. J.

Selective Role of an NH₂-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells

Departments of Urology and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Donald J. Tindall, Departments of Urology, Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-8139; Fax: 507-284-2384; E-mail: tindall.donald{at}mayo.edu.

Systemic prostate cancer therapy requires androgen ablation, which inhibits the production or action of androgens. Prostate cancer ultimately relapses during androgen ablation, and an androgen depletion-independent (ADI) phenotype emerges. Aberrant androgen receptor (AR) activation underlies therapy resistance at this stage of the disease, and mounting evidence implicates the large and highly disordered AR NH₂-terminal domain (NTD) as a key mediator of this activity. In this study, we investigated the role of the NTD transactivation unit 5 (TAU5) domain in mediating AR transcriptional activity in cell-based models of prostate cancer progression. AR replacement and Gal4-based promoter tethering experiments revealed that AR TAU5 had a dichotomous function, inhibiting ligand-dependent AR activity in androgen-dependent prostate cancer cells, while enhancing ligand-independent AR activity in ADI prostate cancer cells. Molecular dissection of TAU5 showed that a WxxLF motif was fully responsible for its ligand-independent activity. Mechanistically, WxxLF did not rely on an interaction with the AR ligand-binding domain to mediate ligand-independent AR activity. Rather, WxxLF functioned as an autonomous transactivation domain. These data show that ligand-dependent and ligand-independent AR activation rely on fundamentally distinct mechanisms, and define WxxLF as the major transactivation motif within the AR TAU5 domain. [Cancer Res 2007;67(20):10067–77]

This article has been cited by other articles:

				A. W. Hsing, L. W. Chu, and F. Z. Stanczyk Androgen and Prostate Cancer: Is the Hypothesis Dead? Cancer Epidemiol. Biomarkers Prev., October 1, 2008; 17(10): 2525 - 2530. [Abstract] [Full Text] [PDF]

				S. M. Dehm, L. J. Schmidt, H. V. Heemers, R. L. Vessella, and D. J. Tindall Splicing of a Novel Androgen Receptor Exon Generates a Constitutively Active Androgen Receptor that Mediates Prostate Cancer Therapy Resistance Cancer Res., July 1, 2008; 68(13): 5469 - 5477. [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]