Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion-independent prostate cancer cells

Scott M. Dehm, Kevin M. Regan, Lucy J. Schmidt, Donald J. Tindall

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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 ARNH 2-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 ART AU5 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 ART AU5 domain.

Original languageEnglish (US)
Pages (from-to)10067-10077
Number of pages11
JournalCancer research
Issue number20
StatePublished - Oct 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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