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PubMed1986

Androgen binding in nuclear matrix of human genital skin fibroblasts from patients with androgen insensitivity syndrome.

Specific sex steroid-binding sites are associated with the salt-insoluble nuclear matrix from which lipids, histones, and chromatin have been extracted. In intact cultured normal human genital skin fibroblasts incubated for 1 h at 37 C with a saturating concentration (2 nM) of [3H]dihydrotestosterone [( 3H]DHT), approximately 50% of the total intracellular androgen receptor-steroid complexes were found in the nucleus. Within isolated nuclei from such cells, 28-49% of the specific androgen receptor binding was associated with the nuclear matrix. The antiandrogen cyproterone acetate inhibited DHT binding within the nuclear matrix. Cultured genital skin fibroblasts from two unrelated patients with receptor-positive complete androgen insensitivity (CAIS, AR+), had normal (approximately 50%) nuclear binding of DHT, and 35% and 45% of it was localized to the nuclear matrix. Genital skin fibroblasts from a patient with receptor-negative complete androgen insensitivity (CAIS, AR-) had no specific DHT binding in isolated nuclei or nuclear matrix. Scatchard analysis of specific DHT binding in the nuclear matrix isolated from cells of normal subjects after an in vitro exchange assay (0 C; 24 h) revealed the presence of saturable (maximum binding, approximately equal to 200 fmol/mg nuclear DNA), high affinity (Kd approximately equal to 1.0 nM) binding sites. By contrast, in the nuclear matrix isolated from cells of a patient with CAIS, AR+, the binding affinity for DHT was 3-fold lower (Kd approximately equal to 3.0 nM). When cytosolic androgen receptor-DHT complexes prepared from cells preincubated at 37 C for 1 h with [3H]DHT were incubated at 0 C for 1 h with isolated nuclei and nuclear matrix in the presence of 0.15 M KCl, 40-60% of specific nuclear binding was associated with the nuclear matrix. In these cell-free in vitro experiments, radiolabeled DHT-receptor complexes prepared from normal or mutant cells were mixed with isolated nuclei and nuclear matrix prepared from cells of normal subjects or patients with CAIS, AR+ or CAIS, AR-. Under these conditions, specific DHT binding in nuclei and nuclear matrix was quantitatively similar in the presence of a mutant (CAIS, AR+) receptor-steroid complex or in the presence of nuclei or nuclear matrix from the mutant cells (CAIS, AR- or AR+) when compared simultaneously with the same subcellular fractions prepared from the cells of normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1992

A single amino acid substitution (Met786----Val) in the steroid-binding domain of human androgen receptor leads to complete androgen insensitivity syndrome.

Androgen receptors (ARs) in two Japanese siblings with complete androgen insensitivity syndrome were characterized, and their molecular bases were investigated. Androgen binding was undetectable in cultured pubic skin fibroblasts from the patients by whole cell assay. Sequence analysis of exons B-H, which encode the DNA- and steroid-binding domains, of the AR gene from these patients using polymerase chain reaction revealed a single nucleotide substitution in exon F, resulting in an amino acid change at 786 from methionine (ATG) to valine (GTG) within the steroid-binding domain of AR. Reconstruction of this mutation by site-directed mutagenesis into human AR cDNA followed by expression in COS-1 cells led to production of the same amount and the same molecular mass of immunodetectable AR protein as those found with expression of the normal human AR cDNA. However, in contrast to wild-type AR expressed in COS-1 cells, the mutant AR showed markedly low affinity of androgen binding by whole cell assay. These results suggest that androgen resistance in these patients is due to the point mutation in the steroid-binding domain of the AR.

Adult↗

PubMed1999

Complete androgen insensitivity caused by a new frameshift deletion of two base pairs in exon 1 of the human androgen receptor gene.

We describe a novel mutation in exon 1 of the androgen receptor gene in a patient with complete androgen insensitivity (CAIS). Endocrine findings were typical for androgen insensitivity (testosterone serum levels in the upper limit of normal males and increased LH serum concentrations). Biochemical investigations in cultured genital skin fibroblasts of the patient showed a normal 5alpha-reductase activity but a complete absence of androgen binding. Western blot analysis revealed no detectable protein product. Sequence analysis of the entire coding region of the androgen receptor gene resulted in the identification of a 2-bp deletion in codon 472, causing frameshift and introduction of a premature stop codon 27 codons downstream of the mutation.

Adult↗

PubMed2001

Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women.

To elucidate the possible role of genetic variation in androgen receptor (AR), estrogen receptor alpha (ER alpha), and ER beta on serum androgen levels in premenopausal women, the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ER alpha gene, and the CA repeat polymorphism of the ER beta gene were studied in a population-based cohort of 270 women. Total testosterone, free testosterone, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, 3 alpha-androstanediol glucuronide, 17 beta-estradiol, LH, FSH, and sex steroid hormone-binding globulin (SHBG) were measured in serum samples obtained in the follicular phase of the menstrual cycle. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH, than women with longer CAG repeat sequences. The CA repeat of the ER beta gene also was associated with androgen and SHBG levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ER alpha gene was not associated with the levels of any of the hormones measured. Our results suggest that the serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ER beta gene, respectively.

Adult↗

PubMed1992

Single base mutations in the human androgen receptor gene causing complete androgen insensitivity: rapid detection by a modified denaturing gradient gel electrophoresis technique.

Mutations of the human androgen receptor (AR) gene impair normal sexual differentiation and development in karyotypic males, resulting in a spectrum of external genital phenotypes ranging from complete female to nearly complete male. Identification and characterization of these mutations can provide valuable information regarding the functional importance of specific amino acids of the AR. To screen for point mutations in the AR gene underlying the phenotypic abnormalities in the androgen insensitivity syndrome (AIS), the eight exons of the AR gene were amplified from genomic DNA using the polymerase chain reaction (PCR) and analyzed by denaturing gradient gel electrophoresis. A computer program, MELTMAP, was used to identify optimum sequences for denaturing gradient gel electrophoresis, and mutation detection sensitivity was enhanced by forming heteroduplexes between control and subject PCR products to create base mismatches. In seven families with complete AIS, single base mutations were found in the region of the AR gene encoding the steroid-binding domain of the receptor. The mutations that converted amino acid 774 from Arg to His and amino acid 864 from Asp to Gly were recreated using site-directed mutagenesis and the mutant ARs expressed in COS 7 and CV1 cells. In both cases, abnormalities of androgen binding and transcriptional activation were consistent with the observed sex phenotype. These results together with others reported previously demonstrate that single amino acid changes within the region encoded by exons D to H of the AR gene can alter androgen binding and are a common cause of complete androgen resistance. The strategy used herein, employing denaturing gradient gel analysis of heteroduplex PCR products, provides a valuable aid to rapid detection of single base mutations in AIS.

Adolescent↗

PubMed1999

Differential induction of androgen receptor transactivation by different androgen receptor coactivators in human prostate cancer DU145 cells.

Recently identified androgen receptor (AR) coactivators were used in this study to determine whether the specificity of sex hormones and antiandrogens could be modulated at the coactivator level. We found that ARA70 is the best coactivator to confer the androgenic activity on 17beta-estradiol. Only ARA70 and ARA55 could increase significantly the androgenic activity of hydroxyflutamide, a widely used antiand rogen for the treatment of prostate cancer. None of the AR coactivators we tested could significantly confer androgenic activity on progesterone and glucocorticoid at their physiological concentrations (1-10nM). We also found that ARA70, ARA55, and ARA54, but not steroid receptor coactivator-1 (SRC-1) and Rb, could significantly enhance the delta5-androstenediol-mediated AR transactivation. Furthermore, in comparing the relative specificity of these coactivators to AR in DU145 cells, our results suggested that ARA70 has a relatively higher specificity and that SRC-1 can enhance almost equally well many other steroid receptors. Finally, our data demonstrated that AR itself and some select AR coactivators such as ARA70 or ARA54 could, respectively, interact with CBP and p300/CBP-associated factors that have histone acetyl-transferase activity for assisting chromatin remodeling. Together, our data suggest that the specificity of sex hormones and antiandrogens can be modulated by some selective AR coactivators. These findings may not only help us to better understand the specificity of the sex hormones and antiandrogens, but also facilitate the development of better antiandrogens to fight the androgen-related diseases, such as prostate cancer.

Androgen Antagonists↗

PubMed1983

In vitro effect of androgen on RNA synthesis in nuclei from androgen-independent subline of Shionogi carcinoma (CS 2).

By serial transplantation of CS 1, a subline of Shionogi carcinoma SC 115, to female mice, another subline was obtained and designated CS2. The subline showed a complete loss of androgen dependency on the growth of the tumor. When male mice bearing the tumor were castrated and treated with testosterone, the activity of RNA polymerase I in isolated nuclei from the tumor hardly varied during the period of the experiments (36 h), while the activity of RNA polymerase II exhibited a transient increase (about 40%) at 6 h after the testosterone injection. The results, together with the previous ones showing 80% and 40% increases in RNA polymerase I activity at 24 h after testosterone administration in the case of SC 115 (androgen-dependent tumor) and CS 1 (less androgen-dependent tumor), respectively, indicate that the stimulation of RNA polymerase I activity by androgen in the tumor tissues is closely related to the androgen dependency on the growth of the tumors.

Androgens↗

PubMed2005

Comparison of different androgen bioassays in the screening for environmental (anti)androgenic activity.

Endocrine disruptors pose a growing threat to human and wildlife health. Validated test systems are required to study the mechanisms by which chemicals may interfere with the endocrine system. In order to identify compounds with (anti)androgenic activity, we used several in vitro bioassays, based on different androgen receptor (AR) functions, including AR transactivation and interaction between the amino-terminal domain and the ligand-binding domain. The AR activity assay, based on activation of the transcription of an androgen-responsive reporter gene in the presence of androgen, proved to excel in terms of high fold induction range and low minimal detection limit. The EC50 value, defined as the concentration that leads to half the maximal response and reflecting the potency of the synthetic androgen R1881 (methyltrienolone), was found to be 250 pM, consistent with the high affinity of this ligand to the human AR. A number of environmental samples were tested in the bioassay. The bioassay also could be used to detect antiandrogenic activity, because known AR-antagonists were able to inhibit R1881-mediated transactivation.

Androgen Antagonists↗

PubMed2006

A novel androgen receptor mutation resulting in complete androgen insensitivity syndrome and bilateral Leydig cell hyperplasia.

Androgens drive male secondary sexual differentiation and maturation. Mutations in the androgen receptor (AR) gene cause a broad spectrum of abnormal phenotypes in humans, ranging from mild through partial to complete androgen insensitivity. We have analyzed the AR gene by using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing and have studied gonads histologically in a familial case of complete androgen insensitivity syndrome. Sequence analysis of the AR gene showed a novel C2578T missense mutation, resulting in the replacement of a highly conserved leucine residue with phenylalanine (L859F) in ligand-binding domain of the receptor. The residue L859, located in helix 10 of the androgen receptor, plays a significant role in overall architecture of ligand-binding pocket. The mutation was absent from the father, normal brother of the patients, and 100 normal males recruited in this study as controls. The inheritance of the mutation in the family clearly shows that C2578T is the underlying mutation for the eventual phenotype in the patients. Histology of patient's gonads showed Leydig cell hyperplasia, with a few or no spermatogonium. It is thought that AR gene mutations result in hormonal imbalance, resulting in the high levels of luteinizing hormone (LH) and ultimately Leydig cell hyperplasia or tumor formation. In the present study, we have reported a rare familial case of Leydig cell hyperplasia despite consistently normal LH levels. The finding will help in giving counseling to this family and prevent the transmission of the mutated X chromosome to the coming generations.

Adolescent↗

PubMed1993

Androgen receptor and mechanism of androgen action.

Androgen receptor is the intracellular protein that mediates biological actions of physiological androgens (testosterone and 5 alpha-dihydrotestosterone). Androgen receptor belongs to a large family of ligand-dependent proteins whose function is to modulate expression of genes and gene networks in a cell- and tissue-specific manner. The present overview describes the structurally important domains of the receptor protein, and discusses several aspects in the structure-function relationship, using naturally occurring receptor mutants in androgen insensitivity patients or experimental animals as examples. In addition, characteristics of androgen receptor expressed in a heterologous system are described, and their potential usefulness in specific molecular studies discussed.

Androgens↗

PubMed2001

[From gene to disease; androgen receptor gene, androgen insensitivity syndrome, and spinal and bulbar muscle atrophy].

Androgen insensitivity is an X-linked disorder of male sexual differentiation resulting from a defective androgen receptor. Spinal and bulbar muscular atrophy (Kennedy's disease) is an X-linked disease, resulting from expansion of the polyglutamine stretch in the N-terminal part of the androgen receptor. Mutation analysis confirms the clinical diagnosis of androgen insensitivity and enables carrier detection and prenatal diagnosis. Kennedy's disease, with its diagnostic problem of clinical variability, is diagnosed or excluded when an expanded CAG-repeat is present or absent in exon 1 of the androgen receptor. Molecular testing can be used for carrier detection and genetic counselling.

Androgen-Insensitivity Syndrome↗

PubMed2002

Androgenic regulation of expression of androgen receptor protein in the perineal motoneurons of aged male rats.

Androgen might regulate expression of androgen receptors (AR) in AR-containing motoneurons in young animals. In the present study, it was examined whether expression of AR was also regulated by androgen in aged animals. Twelve male rats were castrated at 26 months of age. Five days following castration, the animals were treated with testosterone propionate (TP; six males) or vehicle (six males) and killed 2 hours later. Six sham-castrated rats served as controls. AR immunoreactivity was examined in motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in these animals by immunohistochemistry using the polyclonal antibody PG21. In control animals, slightly intense AR immunoreactivity was confined to the nuclei of the motoneurons. AR immunoreactivity was completely eliminated in the motoneurons of castrated rats. In castrated, aged animals treated with TP, the intensity of AR immunoreactivity in the nuclei of SNB motoneurons was increased. Plasma levels of testosterone in castrated, aged animals 2 hours following treatment with TP were significantly greater than those in controls. These results suggest that expression of AR in motoneurons of the SNB in aged male rats is up-regulated in response to androgen and that androgen may be, at least in part, involved in the process of aging of the SNB in male rats.

Aging↗

PubMed2003

Mechanisms and clinical relevance of androgens and androgen receptor actions.

Androgens, principally testosterone and 5alpha-dihydrotestosterone, affect a number of diverse responses in a variety of peripheral target tissues. Their biological actions are mediated by a ligand-dependent nuclear transcription factor, the androgen receptor (AR). The AR is a member of the steroid hormone receptor family, which is found in a variety of tissues, and changes throughout development, aging, and malignant transformation. Recently, cloning and characterization of several AR co-regulators have allowed for cellular and molecular analysis of many different aspects of androgen physiology and pathophysiology. The transcriptional activity of AR is regulated by AR co-regulators, which influence the ligand selectivity and DNA binding capacity of AR. Aberrant co-regulator function due to mutation or altered expression levels may be a contributing factor in the progression of AR-mediated diseases. However, in spite of the intensity of research activity in this area, many interesting questions regarding the fundamental mechanism of AR and co-regulators on androgen-related diseases, such as osteoporosis and androgen insensitive syndrome remain unsolved. In this review, we provide a brief overview of genomic and non-genomic androgens/AR actions, as well as the regulation of their co-regulators. We also explore several intriguing aspects of the molecular biology of AR and co-regulators that are related to clinical diseases.

Androgens↗

PubMed2006

[Age-dependent decrease in plasma androgens, and role of androgens in bone mineral density and bone metabolism].

Circulating plasma testosterone decreases by 0.5-1% per year after 40 age in men. Bone mineral density (BMD) in men also decreases by about 1% per year after age 40-60. Due to progression of an aging society, the frequency of osteoporosis in elderly men is gradually increased. Androgens have a major role in the growth and the maintenance of both cancellous and cortical bone mass in men. Androgen receptor is expressed in osteoblasts, osteoclasts and bone marrow stromal cells. Androgens have been shown to control the bone formation and resorption by regulating the expression and the activity of several cytokines and growth factors through androgen receptor. In addition to these direct actions, through the aromatase activity estrogens converted from androgens are converted to estrogens which act on bone tissues through estrogen receptor and play an important role in the homeostasis of cancellous and cortical bones in men.

Aging↗

PubMedDate not supplied

A G/A polymorphism in the androgen response element 1 of prostate-specific antigen gene correlates with the response to androgen deprivation therapy in Japanese population.

Prostate-specific antigen (PSA) gene expression is regulated by androgen receptor (AR) through androgen response elements (AREs) in the promoter region of the PSA gene. A single nucleotide polymorphism with guanine (G) to adenine (A) substitution is identified at position -158 in the ARE of the PSA gene. The purpose of this study was to investigate the allelic differences in the PSA promoter activity in vitro and the relation to several clinical factors of prostate cancer patients in the Japanese population. No significant differences of promoter activity in luciferase assay and binding activity of androgen receptor were noted between the two alleles in vitro. The PSA -158 G/A polymorphism was determined by PCR amplification and restriction digestion assays in 101 organ-confined prostate cancer (PC) patients who underwent radical prostatectomy and 52 controls with benign prostatic hyperplasia. The results revealed that homozygosity for the A allele in Japanese is less common (only 8.5%) than in ethnic populations. There were no significant differences in serum PSA value at the time of diagnosis, differentiation of cancer, pathological stage, cancer volume or ratio of serum PSA/ cancer volume. However, cancer volume after neoadjuvant endocrine therapy was significantly smaller in GG genotype than in AA + AG genotypes. Our data indicate that the PSA -158 G/A polymorphism has no effect on the PSA promoter activity in vitro and no association with the serum PSA level in Japanese men, however suggest that the patients with GG genotype of ARE1 may be more sensitive to androgen ablation therapy. Taken together, the ARE1 polymorphism in the PSA gene promoter may be one of the biomarkers for response to androgen deprivation therapy.

Aged↗

PubMed1991

Interaction of androgen response elements with the DNA-binding domain of the rat androgen receptor expressed in Escherichia coli.

A fragment of the rat androgen receptor (amino acids 533-637) containing the DNA-binding domain was produced in Escherichia coli as a fusion product with protein A of Staphylococcus aureus. The fusion protein was purified on IgG-Sepharose, a method that does not involve the use of denaturing agents. Approximately 4 mg of fusion protein was obtained from 500 ml of bacterial culture. In gel shift assays, the recombinant DNA-binding domain displays an affinity for a fragment of the long terminal repeat of mouse mammary tumor virus and for an intronic fragment of the gene coding for the C3 component of the androgen-regulated rat prostatic binding protein. In a DNase I footprinting assay, the fusion protein protects a sequence in the C3 fragment that has previously been shown to act as a functional androgen response element. Interestingly, a single base pair mutation in the response element, which abolishes androgen inducibility, also destroys the ability to interact with the recombinant androgen receptor DNA-binding domain.

Androgens↗

PubMed1994

[Non-radioactive SSCP for the detection of androgen receptor gene mutation--a diagnostic tool for androgen resistance].

Point mutations in the androgen receptor gene cause androgen insensitivity syndromes, clinically characterized by masculinization defects in karyotypic males due to endorgan resistance to androgenic steroids. Characterization of these mutations with single strand conformation polymorphism analysis utilizing radioactive PCR can serve as a diagnostic tool for molecular subclassification of these syndromes. It is the basis for genetic counseling and for therapeutic decisions. Here we report an improved non-radioactive single strand polymorphism analysis for rapid detection of androgen receptor gene mutations in affected individuals. In addition to previously reported mutations, 9 patients with clinical features of androgen resistance were studied. While one insertion mutation was detected, in all other patients different point mutations initiating amino acid substitutions were characterized.

Amino Acid Sequence↗

PubMed1995

Androgen up-regulates epidermal growth factor receptor expression and binding affinity in PC3 cell lines expressing the human androgen receptor.

Androgens are required for the optimal growth and development of both the normal prostate and steroid-sensitive prostate cancer. PC3 prostate cancer cell lines stably expressing the human androgen receptor (AR) and possessing an androgen-sensitive phenotype (PC3-hAR) were used to examine the role of the epidermal growth factor receptor (EGFR) in androgen-stimulated prostate cancer cell growth. Epidermal growth factor (EGF) and dihydrotestosterone (DHT) independently induced the growth of PC3-hAR cells. Moreover, EGF and DHT in combination exerted a synergistic effect on PC3-hAR cell growth. DHT-exposed PC3-hAR cells expressed a greater than 2-fold increase in EGFR mRNA and 50% more EGFR protein than controls. Time course radioligand-binding assays confirmed these findings by showing an elevation in EGF binding in the DHT-exposed PC3-hAR cells. In addition, radioligand competition-binding studies revealed a 2-fold increase in EGFR-EGF binding affinity in the PC3-hAR cells after DHT treatment. However, no enhancement of transforming growth factor alpha or EGF expression was detected because DHT did not affect the levels of these cytokines in the PC3-hAR cell lysate or conditioned media. Our observations suggest that DHT increases both EGFR number and receptor-ligand affinity in androgen-sensitive prostate cancer cells and that these effects correlate with increased EGF binding and an enhanced mitogenic response to EGF.

Adenocarcinoma↗