Abstract
The agonist-induced androgen receptor NH(2)- and COOH-terminal (N/C) interaction is mediated by the FXXLF and WXXLF NH(2)-terminal motifs. Here we demonstrate that agonist-dependent transactivation of prostate-specific antigen (PSA) and probasin enhancer/promoter regions requires the N/C interaction, whereas the sex-limited protein gene and mouse mammary tumor virus long terminal repeat do not. Transactivation of PSA and probasin response regions also depends on activation function 1 (AF1) in the NH(2)-terminal region but can be increased by binding an overexpressed p160 coactivator to activation function 2 (AF2) in the ligand binding domain. The dependence of the PSA and probasin enhancer/promoters on the N/C interaction for transactivation allowed us to demonstrate that in the presence of androgen, the WXXLF motif with the sequence (433)WHTLF(437) contributes as an inhibitor to AR transactivation. We further show that like the FXXLF and LXXLL motifs, the WXXLF motif interacts in the presence of androgen with AF2 in the ligand binding domain. Sequence comparisons among species indicate greater conservation of the FXXLF motif compared with the WXXLF motif, paralleling the functional significance of these binding motifs. The data provide evidence for promoter-specific differences in the requirement for the androgen receptor N/C interaction and in the contributions of AF1 and AF2 in androgen-induced gene regulation.
Highlights
Steroid receptors are ligand-activated transcription factors that regulate gene activation through a series of events triggered by high affinity hormone binding and mediated by receptor binding to response element DNA and coactivators
Response Element Specificity of the WXXLF and FXXLF Motif-mediated NH2- and COOH-terminal (N/C) Interaction and Coactivation by TIF2—We investigated whether androgen response regions derived from different enhancer/promoter regions have a similar requirement for the androgen-induced N/C interaction in androgen receptor (AR)-mediated gene regulation
The role of the WXXLF and FXXLF motifs and effects of TIF2 coactivation on luciferase activity were determined using wild-type AR (AR-FXXLF/ WXXLF) or AR in which FXXLF was changed to FXXAA, WXXLF was changed to AXXAA, or both mutations were created in the same protein
Summary
Steroid receptors are ligand-activated transcription factors that regulate gene activation through a series of events triggered by high affinity hormone binding and mediated by receptor binding to response element DNA and coactivators. Using a shorter NH2-terminal fragment than previously described [14], we show that the WXXLF motif interacts in the presence of androgen with the AF2 region of the ligand binding domain. Luciferase reporter vectors were tested that contain enhancer/promoter regions from the androgen-regulated genes, PSA [16, 17], probasin [18], sex-limited protein (pGC⌬9) [19, 20], and MMTV [21,22,23].
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