Prostate cancer is an androgen-dependent malignancy that usually undergoes clinical remission in response to hormone deprivation but eventually relapses after cancer cells develop the ability to grow in the presence of very low levels of androgen or in response to adrenal steroids (25,26). Prostate cancer cells can develop resistance to hormone deprivation by augmenting signaling pathways activated by the androgen receptor (AR). For example, a substantial fraction of prostate cancers amplify the AR gene after treatment with hormone ablation (27,33,53). Hormone deprivation and exposure to antiandrogens can also lead to selection for AR gene mutations that alter response to antiandrogens and broaden the spectrum of ligand agonists (4,8,10,30,36,45,47,48,50,58,59).Androgen receptor activity can also undergo pathological modulation in androgen insensitivity syndromes by disruption of androgen receptor interaction with coactivator proteins that mediate amplification of the androgen receptor transcription signal or by mutations in the coactivator proteins themselves (2, 39). In prostate cancer, mutations in the COOH-terminal region of the androgen receptor can affect the binding of p160 coactivator molecules (18). Hormone-resistant prostate cancer cells may also overexpress coactivators important for androgen receptor signaling (17). Activating mutations in ␤-catenin, a multifunctional molecule responsible for transcriptional activation in WNT signaling, are found in 5% of prostate cancers (3,9,34,56). The potential significance of this finding was underscored by the finding that ␤-catenin interacts with the androgen receptor to enhance androgen receptor transcriptional activation and liberalize ligand specificity (52).␤-Catenin armadillo repeats, particularly repeat six, were shown to bind androgen receptor in a yeast two-hybrid interaction (62). Moreover, androgen caused nuclear localization of ␤-catenin and enhanced ␤-catenin-mediated transcription (35,38). In this report, we show that ␤-catenin binds to the AF-2 region of the androgen receptor. Furthermore, binding is complementary, not competitive, with both the androgen receptor N-terminal domain (NTD) and the p160 coactivator TIF2 and results in amplified transcriptional signals. MATERIALS AND METHODSPlasmids and plasmid construction. pGALD-H encodes the DNA binding domain of the Saccharomyces cerevisiae GAL4 protein (amino acid residues 1 to 147) and the androgen receptor (amino acid residues 624 to 919) (we renamed it GAL4/AR ligand-binding domain [LBD]), and pNLVP-hAR encodes the transcriptional activation domain of the herpes simplex virus VP16 protein (residues 411 to 456) and the full-length androgen receptor (we renamed it VP16/

The signaling/oncogenic activity of beta-catenin can be repressed by activation of the vitamin D receptor (VDR). Conversely, high levels of beta-catenin can potentiate the transcriptional activity of 1,25-dihydroxyvitamin D3 (1,25D). We show here that the effects of beta-catenin on VDR activity are due to interaction between the activator function-2 (AF-2) domain of the VDR and C terminus of beta-catenin. Acetylation of the beta-catenin C terminus differentially regulates its ability to activate TCF or VDR-regulated promoters. Mutation of a specific residue in the AF-2 domain, which renders the VDR trancriptionally inactive in the context of classical coactivators, still allows interaction with beta-catenin and ligand-dependent activation of VDRE-containing promoters. VDR antagonists, which block the VDRE-directed activity of the VDR and recruitment of classical coactivators, do allow VDR to interact with beta-catenin, which suggests that these and perhaps other ligands would permit those functions of the VDR that involve beta-catenin interaction.

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