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/

Mifepristone is a potent antagonist of steroid hormone receptors such as glucocorticoid and progesterone receptors. We investigated the potential for mifepristone to act as an antiandrogen and compared it with partial androgen receptor (AR) agonists and antagonists, in particular bicalutamide. Mifepristone was an effective antiandrogen in vitro that inhibited transcription from three androgen-responsive promoters and blocked the agonist R1881 in a dose-dependent manner. Like bicalutamide, mifepristone also antagonized the action of androgen receptor with a (T877A) mutation. Mifepristone competed effectively with R1881 with a relative binding affinity comparable to that of cyproterone acetate, and much higher than that of hydroxyflutamide and bicalutamide in a binding assay. Mifepristone could effectively induce the binding of the herpes simplex viral protein 16/AR fusion protein to the hormone response elements in the murine mammary tumor virus-luciferase reporter. With either wild-type or T877A mutant AR, mifepristone alone was unable to induce any detectable interaction with coactivators transcriptional intermediary factor-2 or beta-catenin but could inhibit the R1881-induced binding of AR to transcriptional intermediary factor-2 and beta-catenin. Similarly, mifepristone could inhibit the R1881-induced N/C-terminal interaction in a dose-dependent manner even though mifepristone alone has no effect on the N/C-terminal interaction of AR. We found that mifepristone could induce a strong interaction between AR and corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors in both transactivation and two-hybrid assays to a greater degree than hydroxyflutamide, cyproterone acetate, and bicalutamide. The AR-corepressor interaction was also seen in coimmunoprecipitation assays. Finally, mifepristone at high concentrations induced a low level of prostate-specific antigen expression in LNCaP and antagonized prostate-specific antigen expression induced by R1881. Mifepristone also antagonized R1881 action on the growth of LNCaP prostate cancer cells.

Summary Dendritic cells (DCs) are antigen‐presenting cells that capture, process, and present antigens to lymphocytes to initiate and regulate the adaptive immune response. DCs detect bacteria in skin and mucosa and migrate into regional lymph nodes, where they stimulate antigen‐specific T and B lymphocyte activation and proliferation. DCs direct CD4 T cells to differentiate to T‐cell subsets such as T helper cells types 1, 2, and 17, and regulatory T cells. The periodontium is chronically exposed to oral bacteria that stimulate an inflammatory response to induce gingivitis or periodontitis. DCs play both protective and destructive roles through activation of the acquired immune response and are also reported to be a source of osteoclast precursors that promote bone resorption. FOXO1, a member of the forkhead box O family of transcription factors, plays a significant role in the activation of DCs. The function of DCs in periodontal inflammation has been investigated in a mouse model by lineage‐specific deletion of FOXO1 in these cells. Deletion of FOXO1 reduces DC protective function and enhances susceptibility to periodontitis. The kinase Akt, phosphorylates FOXO1 to inhibit FOXO activity. Hence the Akt–FOXO1 axis may play a key role in regulating DCs to have a significant impact on periodontal disease.

No abstract