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The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract causes spinal bulbar muscular atrophy (Kennedy disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Two alternatively spliced variants encoding distinct isoforms have been described. 4-androstenedione administration in high doses to hypogonadal men increases testosterone levels, fat free mass, and muscle strength and binds to AR. 4-estren-3alpha17beta-diol binds recombinant AR with 10-fold higher affinity than either estrogen receptor (ER)-alpha or ERbeta. A polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. A significant genotype-phenotype association exists in Klinefelter patients: androgen effects on appearance and social characteristics are modulated by the androgen receptor CAGn polymorphism. AR N-terminal(1-34) suppressed both androgen-dependent AR N-to-C interaction and prostate specific antigen transcription and also caused delaying translocation to the nucleus and the decreasing stability of the AR were inhibition to enter into S phase. AR acetylation promoted cell survival and growth of prostate cancer cells. AR and PIAS3 regulate the STAT3-mediated transcriptional activity by their physical protein-protein competition on STAT3. AR and estrogen receptor beta are important in relatively early coronary atherosclerosis. AR containing 51 glutamine repeats showed a consistent, though minimal, reduction in its ability to inhibit beta-catenin-mediated transcription, in comparison to a non-pathogenic form with 20 repeats. AR is a functional component of the mechanism through which progesterone antagonists induce endometrial antiproliferative effects in the presence of estrogens. AR is controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line. AR is expressed in several cell types in human skeletal muscle, including satellite cells, fibroblasts, CD34+ precursor cells, vascular endothelial, smooth muscle cells, and mast cells. AR mutants found in prostate cancer had different functional alterations, which might play an important role in the progression of prostate cancer. AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT. AR repeat length may be partly responsible for the increased risk for early-onset breast cancer in women who use OCs. AR transcriptional activity is negatively regulated by CHIP, which promotes AR degradation. AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment. AR trinucleotide polymorphism is associated with leiomyoma susceptibility. ARA70 is a coactivator for estrogen receptor alpha (ERalpha) and may represent a functional link between ERalpha/androgen receptor (AR) modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells. Almost all of the amino acids located at the 13-residue C-terminal end of the androgen receptor participate in its ligand binding function and consequently in its transcriptional activation. Although further studies are needed to elucidate the possible role of specific CAG/GGC combinations as a causative factor, these data suggest a possible association between androgen receptor gene polymorphisms and cryptorchidism. An R840S mutation on exon 7 of the AR ligand-binding domain was characterized in an X-linked androgen insensitivity syndrome patient. An androgen receptor gene mutation (E653K) in a family with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency as well as in partial androgen insensitivity. An association exists between CAG repeat lengths and impaired spermatogenesis in azoospermic males. Androgen Receptor requires proteasome activity in prostate tumor cells. Androgen receptor (AR) CAG repeat not associated with migraine susceptibility. Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men. Androgen receptor is recruited to the promoter of the c-FLIP gene in the presence of androgens. Androgen receptor is targeted to distinct subcellular compartments with treatment by different antiandrogens. Androgen receptor may play important role in onset of DNA synthesis in prostate cancer cells by regulating expression and stability of Cdc6, critically required for assembly of pre-replication complex. Androgen receptor mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide resistance to prostate cancer. Androgen receptor mutation with antiandrogen withdrawal response or survival rate is not specific. Androgen receptor over-expression is associated with gastric cancer. Androgen receptors were only seen in hair follicle dermal papilla cells and the basal cells of the sebaceous gland. Androstanediol is a stronge activator of mutant AR in prostate cancer cells and induces more cell proliferation. Bisphenol A can serve as a potential ""hormone sensitizer"" of the mutant ARs present in advanced prostate adenocarcinomas, thereby possibly contributing toward therapeutic relapse. CAG polymorphic repeat lengths in androgen receptor gene among Japanese prostate cancer patients: potential predictor of prognosis after endocrine therapy. CAG/CAA repeat lengths in androgen receptor gene may provide useful marker for clinically significant prostate cancer. CDK6 may play an important role in the development and/or progression of a subset of human prostate cancers by stimulating the activity of the AR. Candidate gene for benign prostatic hyperplasia. Characterization of androgen receptor and nuclear receptor co-regulator expression in human breast cancer cell lines exhibiting differential regulation of kallikreins 2 and 3. Chip overexpression reduced the rate of AR degradation, consistent with an effect on AR folding,Chip affected AR folding was further supported by the finding that the effects of exogenous Chip were reproduced by a mutant lacking the U box. Coding & splice junctions of the androgen receptor gene were scanned in genomic DNA samples from psychiatric patients. 2 variants affecting protein structure & expression were found: R726L in 1 of 17 scanned alcoholics, & P516S in 1 of 3 phobia patients. Comparison of fertile men and those with azoospermia on the basis of CAG repeats revealed that the number of CAG repeats in both groups were similar. Complete androgen insensitivity syndrome is caused by a novel mutation in the ligand-binding domain. Conformational analysis of the androgen receptor amino-terminal domain involved in transactivation. Influence of structure-stabilizing solutes and protein-protein interactions. Conserved hydrophobic residues are important for receptor-dependent gene transcription and that M244, L246 and V248 are part of the binding interface for TFIIF. DHT may play more important roles than testosterone in the regulation of androgen action in endometrial cancer and normal human endometrium, especially in the secretory phase, in which both AR and 5alpha-reductase are increased. DNA interaction in the context of the general mechanisms that dictate the sequence-specificity of DNA-binding and dimerization of the nuclear receptors. Data indicate that growth factors are unable to initiate the nuclear translocation of androgen receptors in the absence of androgens or to induce ligand-independent transcriptional activity. Data report the identification of Rad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-androgen receptor transactivation in prostate cancer cells. Data show that steroid receptor coactivator-1 (SRC-1) enhanced ligand-independent activation of the AR by IL-6 to the same magnitude as that obtained via ligand-dependent activation, and that activation required MAPK. Data show that stimulation of the RhoA effector protein kinase C-related kinase (PRK) signalling cascade results in a ligand-dependent superactivation of androgen receptors both in vivo and in vitro. Data show that the haplotype distribution of CAG and GGC repeat lengths is different in men with idiopathic infertility compared to fertile normozoospermic men. Data suggest that 1,25-dihydroxyvitamin D(3) actions on normal prostate cells may be mediated independently through androgen receptors and vitamin D receptors. Data suggest that acetylation and phosphorylation of the androgen receptor (AR) are linked events and that the conserved AR lysine motif contributes to a select subset of pathways governing AR activity. Data suggest the ligand-binding domain has a role in maintaining the stability of androgen receptor-DNA complexes. Deletion of the polyglutamine repeat positively affected the interactions of the ligand-binding domain with the amino-terminal domain as well as the recruitment of the p160 coactivator SRC-1e to the amino-terminal domain of the AR. Despite S597R mutation and severe undermasculinization, as seen in the baby, normal male phenotype for age could be achieved with treatment. Domain interactions between coregulator ARA(70) and the androgen receptor (AR); structure activity relationship. EGR1 binds to the androgen receptor (AR) in prostate carcinoma cells, and an EGR1-AR complex can be detected. FLNa interfered with androgen receptor (AR) interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. Fifteen different mutations were identified, including five (S119X, T602P, L768V, I898F, and P904V) that have not been described previously. Full binding of androgen to the polyglutamine-expanded N-terminal domain of the mutant AR leads to structural alteration with nuclear translocation that eventually results in the onset of spinal and bulbar muscular atrophy. GGC and CAG trinucleotide repeat lengths in the androgen receptor gene polymorphism is associated with esophageal cancer risk. GGC and StuI polymorphism is found on the androgen receptor gene in endometrial cancer. H3-K4 methylation at the human prostate specific antigen (PSA) locus following gene activation and repression via androgen receptor. IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. In contrast to other studies, we did not find a statistically significant relationship between the size of the androgen receptor CAG repeat and impaired sperm production in Tunisian population. In situ shortening of CAG repeat lengths in prostate cancer(PCA), prostatic intraepithelial neoplasia, and postatrophic hyperplasia(PAH). Frequency of CAG shortening was significantly higher in PAH than in PCA. Inhibition of glycogen synthase kinase-3 reduced the growth of AR-expressing prostate cancer cell lines. Interactions between AR and beta-catenin contribute to prostate cell growth in vivo. Ku is a transcriptional recycling coactivator of the androgen receptor in prostate cancer cells. LATS2 may play a role in AR-mediated transcription and contribute to the development of prostate cancer. Long CAG repeats in the AR gene are not associated with infertility in Finnish males. Longer AR CAG repeats are more common in men with breast cancer than in the control male population. Androgen hyposensitivity, caused by long AR CAG repeats, may increase the risk of breast cancer in men. Mapping the region of cyclin D1 required for binding and repression of the androgen receptor in prostate cancer. Missense substitution at M807 is associated with androgen insensitivity syndrome. Molecular studies performed on eight individuals with AIS were reported. Exon-specific polymerase chain reaction (PCR), single-strand conformation polymorphism, and sequencing analyses, were performed in exons 2 to 8 of the AR gene. Mutations in androgen receptor is associated with Androgen-Insensitivity Syndrome. NCoR is a physiological regulator of the AR; the N-terminal surface of the AR-mediating NCoR recruitment was distinct from tau5 and from the FXXLF motif that mediates agonist-induced N-C-terminal interaction. Novel nonsense mutations that introduce premature termination codons in the AR gene in Australian patients with complete androgen insensitivity syndrome. Orphan receptor TR2 may function as a negative modulator to suppress AR function in prostate cancer. Further studies on how to control TR2 function may result in ability to modulate AR function in prostate cancer. Our results suggest that short CAG repeats are associated with an increased prostate cancer risk in Hispanic men. Our study thus suggests a functional cooperation between AR and Stat5. PTEN, via distinct mechanisms, differentially regulates androgen receptors in various stages of prostate cancers. Pim1 and Etk are required for IL6-induced activation of androgen receptor-mediated transcription in prostate cancer. Polymorphisms within the gene are biomarkers for the development of benign prostatic hyperplasia and benign prostatic enlargement(SRD5A2). Positive independent correlation of the CAG repeat number with body fat content, leptin and insulin. Promoter methylation of AR occurs in a differentiation stage-selective manner in follicular non-hodgkin's lymphoma. Results describe a novel mutation in exon 7 of the androgen receptor gene in a patient with partial androgen insensitivity syndrome. Results do not support a common role for the androgen receptor gene exon 1 CAG repeat in type 1 diabetes mellitus susceptibility; however, an effect of a disease variant in linkage disequilibrium could be detected. Results suggest that p54(nrb) functions as a coactivator of androgen receptors that potentiates transcription and possibly splicing. Results suggest that the conserved AR acetylation site contributes to a pathway governing prostate cancer cellular survival, as AR acetylation mutants are defective in MEKK1-induced apoptosis. Review. Molecular genetics & structural analysis allow a better understanding of the structure/function relationship of the androgen & its role in androgen insensitivity syndrome, hormone-resistant prostate cancer, Kennedy's disease & male infertility. S-phase fraction was significantly higher in prostate tumors with high AR density. SENP1's ability to enhance AR-dependent transcription is not mediated through desumoylation of AR, but rather through its ability to deconjugate histone deacetylase 1 (HDAC1), thereby reducing its deacetylase activity. SMRT and DAX-1 repress agonist-dependent activity of androgen receptors. SNP on codon 211 in the AR gene may not have an important role in the carcinogenesis of human renal cell cancers. SWI/SNF function potently regulates core AR target gene promoter activation, with a preference for hBRM-containing complexes. Stabilization of androgen receptor protein is induced by agonist, not by antagonists. Statistical analysis revealed no actual link between the length of the CAG tract and a reduction of spermatogenesis in a cohort of infertile patients of Irish ethnic origin. Strong nuclear immunoreactivity for AR and ERbeta was found in the secretory epithelium of apocrine glands in axilla. Structural basis for the glucocorticoid response in a mutant human androgen receptor. Substantial qualitative and quantitative differences in prostate specific antigen expression and AR occupancy of the prostate specific antigen enhancer were observed when dihydrotestosterone and ligand-independent activations of the AR were compared. Testosterone-bovine serum albumin was also effective in inducing apoptosis of DU145 human prostate cancer cells, negative for intracellulaar AR, but expressing cell membrane AR sites. The < 21 CAG and GGN = 23 combination of repeats may confer a lower risk of infertility to the carriers. Androgen sensitivity may be higher among carriers of the GGN = 23 allele compared to the GGN = 24 allele. The AR gene (CAG)n exhibits polymorphism among normal male population and the present work could serve as a basis for further exploration of its pathological and genetic significance. The CAG repeat polymorphism in the first exon of the androgen receptor (AR) gene is associated with reduced bone mass and increased risk of osteoporotic fractures in women. The CAG repeats in exon 1 of the androgen receptor gene are longer in endometrial cancer patients. The FXXLF motif mediates androgen receptor-specific interactions with coregulators. The ability of a short GGC repeat to enhance androgen action provides a biologically plausible mechanism to account for reports that a short GGC repeat in the AR gene is a risk factor for prostate cancer. The aggregation and localization of the truncated form, with or without an expanded polyglutamine tract, is differentially controlled by Glucocorticoid receptor mutants. The binding of HuR, CP1, and CP2 to AR mRNA suggests a role for each of these proteins in the post-transcriptional regulation of AR expression in cancer cells. The interaction of the androgen receptor N-terminal activation domain AF1 with the transcription factor TFIIF complex imposes a functional conformation in the AF1 domain, which facilitates the formation of an assembly of proteins with AF1. The loss of AR expression is associated with invasive bladder cancer. The loss of the androgen receptor expression together with the observed loss of other steroid hormone receptors in BRCA1-mutated tumors may lead to a hormone-independent growth or to anti-hormone resistant growth of these tumors. The presence of short androgen receptor alleles and the G allele of the prostate specific antigen gene may contribute to the development of prostate cancer in a 47,XXY patient. The repeat polymorphisms in the AR gene are associated with bone mass in women with high levels of sex-hormone binding globulin. The transactivational activity of AR was shown to be affected by the size of the trinucleotide-repeat-regions (CAG and GGC) within the gene. There is a coregulatory role for the TRAP-mediator complex in receptor-mediated gene expression. There is no evidence of increased risk of prostate cancer among balck men with fewer CAG repeats. These data failed to confirm that common genetic variation in the AR gene locus influences risk of prostate cancer. These findings support the theory that short trinucleotide repeat genotypes of the AR gene protect against breast cancer. These results demonstrate that activation of the human AR NTD by IL-6 was mediated through MAPK and STAT3 signal transduction pathways in LNCaP prostate cancer cells. These results suggest a model for the functional coordination between the promoter and enhancer in which communication between these elements is established through shared coactivators in the AR transcription complex. Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins. We conclude that more numerous CAG repeats do not directly cause oligozoospermia and propose that men with longer CAG repeats might be more prone to develop infertility in response to any pathogen/epigenetic factors. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. Women homozygous for the Androgen Receptor CAG repeat were over-represented in ovarian cancer patients reinforcing recent suggestions that AR may have a role in ovarian carcinogenesis. A direct correlation exists between the CAG repeat length in the exon 1 of the AR gene and the risk of being azoospermic. A new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription. A triple complex between AR, p85alpha, and Src is required for androgen-stimulated PI3K/Akt activation. Activation function-1 domain of androgen receptor contributes to the interaction between subnuclear splicing factor compartment and nuclear receptor compartment. Androgen can regulate the nuclear export signal and, subsequently, the NLS of the AR, providing a mechanism by which androgen regulates AR nuclear/cytoplasmic shuttling. Androgen receptor CAG repeats in both black and white patients do not appear to be a strong indicator of prostatic cancer risk. Androgen receptor and DXS15-134 markers show a high rate of discordance for germline X chromosome inactivation in patients with breast or ovarian cancer. Androgen receptor downregulates E-cadherin-mediated cell adhesion and promotes apoptosis of prostatic cancer cells. Androgen receptor has a capacity to activate transcription in a ligand-independent manner. Androgen receptor has a site in the ligand binding domain that is involved in estrogen induction of androgen receptor trans-activation. Androgen receptor transactivation and coactivation by TIF2/GRIP1 in recurrent prostate cancer is increased by EGF signaling through MAPK. Androgen receptor transactivation requires activating signal cointegrator-2 and the tumor suppressor retinoblastoma. Androgen receptor, Hsp70, and Bag-1L are all targeted to the androgen response elements of the gene that encodes prostate-specific antigen. Androgen receptor-mediated transactivation and cell growth is suppressed by the glycogen synthase kinase 3 beta in prostate cells. Androgens can regulate PTHrP production, and the androgen effect on PTHrP is mediated at least in part by transcriptional regulation via the androgen receptor. Association between GGN length and the risk of cryptorchidism and penile hypospadias. Can promote nuclear translocation of beta-catenin in LNCaP and PC3 prostate cancer cells. Certain types of age-related changes in ageing men were associated with the length of the AR gene CAG repeat, suggesting that this parameter may play a role in setting different thresholds for the array of androgen actions in the male. Changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling in prostate cancer. Concluded that AR-CAG repeat length does not constitute an important factor for the genetic predisposition to endometriosis. Contribution of genetic polymorphism of oestrogen and androgen receptor (AR) genes in male infertility. Cyclin D1 binding to the androgen receptor NH2-terminal domain inhibits activation function 2 association. Data suggest an important role of AR45 in modulating AR function and add a novel level of complexity to the mode of action of androgens. Data suggest that AR interacting peptides and/or AR coregulators may utilize the (F/W)XXL(F/W) and FXXLY motifs to mediate their interaction with AR and exert their influences on AR transactivation. Diabetes or glucose impairment was more common than previously reported and, like gynecomastia, did not correlate with size of triplet repeats. Different populations may show different numbers of CAG repeats. Differential expression of AR, ERalpha and ERbeta in dermal papilla of hair follicles. Earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. Exon 5 of the androgen receptor has a role in androgen binding, as shown by analysis of insertion/deletion mutation in the androgen receptor. Function inhibited by the reproductive orphan nuclear receptor DAX-1. Glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Identification as a coactivator for the androgen receptor [p102 U5 small nuclear ribonucleoprotein particle-binding protein]. Identification as a coactivator for the receptor [p102 U5 small nuclear ribonucleoprotein particle-binding protein]. Identification of an inhibitory domain located in an 81-amino acid segment lying upstream of the DNA-binding domain (DBD) that interacted directly with DBD and repressed DBD binding to the androgen response element. Interaction with Cdc25B may contribute to prostate cancer development. Interactions between AR, Smad3, and Smad4 may result in the differential regulation of the AR transactivation, which further strengthens their roles in the prostate cancer progression. Major sites of AR phosphorylation. Molecular dynamic modeling to create four-dimensional models of each of the mutant receptors. Neuroprotection. No statistically significant relationship between the length of the CAG repeat of the AR gene and idiopathic impaired sperm production was observed in the Turkish population, contrary to the findings from Caucasian and North American population studies. Polymorphic CAG repeats in the gene and prostate cancer risk. Poor reproductive performance observed in women with PCOS may be due to the concomitant increase and elevations in endometrial AR. Presence of both the amino- and carboxyl-terminal domains in the AR is essential for the completion of a transcriptionally active form with coactivators and intranuclear compartmentalization common to the steroid hormone receptors. Present study shows that the AR isoform pattern from AR de novo synthesis is directly linked to differential phosphorylation of a distinct set of sites; after mutagenesis of these sites, no major change in functional activity of the AR was observed. Regulation of androgen receptor by PI3 kinase. Results suggest that hAR AF-1 recruits co-activators previously known only to interact with the AF-2 domain. Review elucidates the molecular functions of the androgen receptor and its role in prostate cancer and examines how the mechanism of androgen action has played a role in the translation of new therapies. Review of NH(2)-terminal and carboxyl-terminal interaction in the androgen receptor. Review: role of androgen receptor CAG repeat polymorphism as modifier of carcinogenesis. Role in blood pressure. Role in spinal and bulbar muscular atrophy [review]. Side chains unique to the AR-ligand binding domain rearrange to bind either the bulky FXXLF motifs or the more compact LXXLL motifs. Significance for endocrine therapy in prostatic cancer (REVIEW). Stained sections throughout male genital development documented the expression of AR and 5 alpha-reductase type 2 in the phallus. Study suggests that the androgen receptor gene microsatellite polymorphism may be a candidate genetic marker for risk of osteoporosis in postmenopausal women. The AR functions as a ligand-regulated transcription factor. The androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells. The androgen receptor-CAG alleles may contribute to hepatocellular carcinoma predisposition among women through a mechanism different from that for men. The effects of AR NH2- and COOH-terminal interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. The expression of the Kennedy's disease mutation combined with a second allele with a large but normal CAG repeat sequence may have contributed to the motor neuron degeneration displayed in the heterozygote female. The role of AR in inhibiting E(2) action at genomic level in MCF-7 cells. There is a direct interaction between the AR DNA binding domain (DBD) and Tcf4.
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