Disease relevance of Ar

• We have been investigating the mechanisms underlying androgen-independent prostate cancer in Nkx3.1;Pten mutant mice, which display salient features of the disease, including a requirement for wild-type androgen receptor (AR) signaling [1].
• Binding of androgen-receptor complexes to alpha 2u-globulin genes and to the long terminal repeat of mouse mammary tumor virus [2].
• One may speculate that AR antagonists might be useful in the treatment of obesity in men [3].
• Premature ovarian failure in androgen receptor-deficient mice [4].
• Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells [5].

Psychiatry related information on Ar

• Spinobulbar muscular atrophy is a progressive motor neuron disease caused by abnormal polyglutamine tract expansion in the androgen receptor (AR) gene, and is part of a family of central nervous system (CNS) neurodegenerative diseases, including Huntington's disease (HD) [6].
• Treatment with the estradiol receptor antagonists, tamoxifen (TAM) (10 mg kg(-1); s.c. or 0.1 microg; i.cist.) and 4-hydroxytamoxifen (10 mg kg(-1); s.c.), or the androgen receptor antagonist, cyproterone (10 mg kg(-1); s.c. or 1 microg; i.cist.), did not influence the protective effect of betaE2 or TES on ouabain-induced amnesia [7].
• Titration of monoclonal AR antibody, F39.4.1, and concentration and reaction time of substrate were optimized using color video image analysis [8].

High impact information on Ar

• To study the stability of a trinucleotide repeat and to develop an animal model of one of these disorders, spinal and bulbar muscular atrophy (SBMA), we have generated transgenic mice carrying either the normal or expanded repeat human androgen receptor (AR) gene [9].
• Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice [9].
• In the androgen-insensitive Tfm mouse, the gland anlagen are resistant to the testosterone action [10].
• On the other hand, in combination with wild-type mesenchyme, the androgen-insensitive Tfm epithelial buds were destroyed [10].
• To analyze cellular interactions in this process, we isolated the mammary gland anlagen from Tfm- and wild-type embryos [10].

Chemical compound and disease context of Ar

• Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein [6].
• Nonaromatizable AR-selective agonists potently stimulate hypertrophy and induce significant myometrial expansion distinct from that induced by 17beta-estradiol (E2) [11].
• In the external genitalia the stimulatory effect of testosterone is reduced leading to various degrees of feminization correlating with the proportion of Tfm cells present [12].
• We show that BAF57 is expressed in the luminal epithelia of the prostate and is required for AR-dependent transactivation in prostatic adenocarcinoma cells [13].
• Because toremifene prevented prostate cancer in a milieu of elevated blood free testosterone levels with no change in prostate androgen receptor expression, the mechanism of toremifene's chemopreventive activity may be through nonandrogenic pathways, such as estrogen receptor signaling [14].

Biological context of Ar

• The role of meiosis on AMH expression was investigated in Tfm and in pubertal XXSxrb mice, in which germ cells degenerate before meiosis [15].
• The androgen receptor (AR) controls several biological functions including prostate cell growth and apoptosis [16].
• Together, our PM-AR(-/y) mice provide in vivo evidence for the requirement of functional AR in peritubular myoid cells to maintain normal Sertoli cells function and peritubular myoid cell contractility, thus ensuring normal spermatogenesis and sperm output [17].
• Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AR gene, AR(GAL4DBD), which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator) [18].
• AR knockout males displayed a complete androgen insensitivity phenotype [19].

Anatomical context of Ar

• In neonatal mice, AMH was not inhibited by intratesticular testosterone, due to the lack of expression of the androgen receptor in Sertoli cells [15].
• Forced activation of either Akt or Erk signaling in an androgen-responsive prostate cancer cell line promotes hormone-independent but AR-dependent growth in culture [1].
• Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells [17].
• We propose that androgen independence emerges by means of epithelial-stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma [1].
• Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions [18].

Associations of Ar with chemical compounds

• In immature normal and in androgen-insensitive Tfm mice, follicle stimulating hormone (FSH) administration resulted in elevation of AMH levels, indicating that AMH secretion is stimulated by FSH in the absence of the negative effect of androgens [15].
• A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice [20].
• Furthermore, the effects of 17beta-estradiol could not be mediated by the AR, and the effects of 5alpha-dihydrotestosterone were increased rather than decreased in ER-inactivated mice [21].
• Agonist-bound AR was required because the AR antagonists casodex and hydroxyflutamide failed to translocate beta-catenin [22].
• Similarly to androgen-independent PCa in patients, the relapsed xenografts and cell line expressed AR and were resistant to treatment with bicalutamide [23].

Physical interactions of Ar

• The region of RAP 01 which binds androgen-receptor complexes has previously been shown to interact with glucocorticoid receptors and contains a 17 bp sequence homologous with the consensus sequence for glucocorticoid-receptor binding [2].
• Our data reveal that BAF57 can directly bind to the AR and is recruited to endogenous AR targets upon ligand activation [13].
• The use of tfm/y mice permitted study of the estrogen-receptor complex in the absence of androgen receptor [24].
• Taken together our data suggest that, in vivo, Kgf may interact with androgen receptor signalling but it is not a direct target of androgen action [25].

Regulatory relationships of Ar

• Finally, transgenic overexpression of PTHrP within the basal epidermis induces AR and tenasin C expression within the ventral dermis, suggesting that ectopic expression of PTHrP can induce the ventral mesenchyme to express mammary mesenchyme markers [26].
• Next, we examined whether EGF enhanced AR mediated transcriptional activity in the developing tract [27].
• In summary, the trabecular bone is preserved both by a testicular factor, presumably testosterone acting via AR and by an estrogen-induced activation of ER-alpha [28].
• The AR gene itself is regulated by AR but not GR in a variety of cell types, including osteoblast-like cells, as shown here [29].
• Examination of sections of kidneys from Tfm/Y mice before and after testosterone (T) treatment revealed that only the juxtamedullary tubules expressed KAP mRNA and that T increased the level of KAP mRNA in these cells [30].

Other interactions of Ar

• ERalpha, but not AR or ERbeta, activation resulted in preserved thickness, volumetric density, and mechanical strength of the cortical bone [21].
• Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice [18].
• These data suggested that the androgen receptor-independent induction of KAP gene expression in these animals was mediated by an estrogenic metabolite of testosterone, since dihydrotestosterone cannot be aromatized to an estrogenic form [31].
• We further show that this 1,25 D(3)-mediated inhibition of PIN was coincident with up-regulation of vitamin D receptor expression in the prostatic epithelium of the mutant mice, as well as in CASP prostate epithelial cell lines developed from these mice, while having no effect on androgen receptor expression or androgen receptor signaling [32].
• Modulation of androgen receptor (AR)-mediated transcriptional activity by EGF in the developing mouse reproductive tract primary cells [27].

Analytical, diagnostic and therapeutic context of Ar

• A yeast two-hybrid assay was employed to identify androgen receptor (AR) protein partners in gonadotropin-releasing hormone neuronal cells [22].
• In Tfm/Y androgen receptor-deficient mice, KAP mRNA was detected by in situ hybridization in a subpopulation of these cells only in the S3 segment of the proximal tubules in the outer medulla [31].
• RESULTS: AR inactivation or orchidectomy induced a similar degree of trabecular bone loss (-68% and -71%, respectively) [33].
• Immunofluorescence was also performed for androgen receptor and cytokeratin 14 expression [34].
• Castration of hosts induced apoptosis in the AR-negative Tfm prostatic epithelium with an epithelial apoptotic index virtually identical to prostatic tissue recombinants containing wild-type epithelium [35].

References