title: Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion independent prostate cancer cells.
abstract: 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.
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Regan
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Schmidt
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000172:deficiency*; D000818:Animals; D001483:Base Sequence; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D008024:Ligands; D011944:Receptors, Androgen