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PubMed1998

Intermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity.

Structural alignment of the human androgen receptor dimer was investigated by introducing steroid binding domain mutations that cause partial or complete androgen insensitivity into fusion proteins containing the full-length androgen receptor or the steroid binding domain. Most of the mutants had unchanged apparent equilibrium androgen binding affinity and increased dissociation rates of [3H]methyltrienolone and required increased dihydrotestosterone concentrations for transcriptional activation. In a 2-hybrid protein interaction assay in mammalian cells, the steroid binding domain interacts with an NH2-terminal-DNA binding domain fragment and with the full-length androgen receptor at physiological androgen concentrations in a dose-dependent manner. However, mutations at Val-889 and Arg-752 disrupt the NH2-/carboxyl-terminal interaction when introduced into the steroid binding domain fragment but not when present in the full-length androgen receptor. The N-C bimolecular interaction reduces the dissociation rate of bound androgen and slows the degradation rate of the carboxyl-terminal steroid binding domain fragment. The results suggest that steroid binding domain residues Val-889 and Arg-752 are critical to the NH2-/carboxyl-terminal interaction and that an intermolecular N-C interaction occurs during receptor dimerization that results in an antiparallel arrangement of androgen receptor monomers.

Androgens↗
PubMed1995

Characterization of alternative amino acid substitutions at arginine 830 of the androgen receptor that cause complete androgen insensitivity in three families.

We have studied two different missense mutations at arginine-830 in exon 7 of the human androgen receptor (hAR) gene that cause complete androgen insensitivity (CAIS) in three families. These substitutions result from point mutations at nucleotide 2489: a G-->T transversion causes Arg830Leu and a G-->A transition causes Arg830Gln. Genital skin fibroblasts of the patients have negligible androgen-binding capacity. The mutations were recreated in an hAR cDNA expression vector that was transiently transfected into COS-1 cells. Both mutant androgen receptors have increased dissociation rate constants and apparent equilibrium rate constants when measured with 5 alpha-dihydrotestosterone or the synthetic, nonmetabolizable androgens, mibolerone or methyltrienolone. The mutant androgen-binding activities share a distinctive thermal misbehavior. At 37 degrees C R830Q and R830L are about 40% and 10% of normal, respectively. At 22 degrees C both mutants gain androgen binding while the normal decreases by 20%; for R830Q the augmented value approaches 60% of the normal. During prolonged 18 h incubation at 37 degrees C, androgen binding of the normal AR is stable while that of both mutants decreases by at least 85%. Both mutants have a very reduced ability to transactivate a cotransfected androgen-responsive reporter gene, but R830Q is better than R830L. We conclude that arginine-830 is important for A-R complex stability, and that its replacement by glutamine or leucine yields distinctive functional aberrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome.

Partial androgen insensitivity syndrome (PAIS) is caused by defects in the androgen receptor gene and presents with a wide range of undervirilization phenotypes. We studied the consequences of six androgen receptor ligand-binding domain mutations on receptor function in transfected cells. The mutations, Met742Ile, Met780Ile, Gln798Glu, Arg840Cys, Arg855His and Ile869Met, were identified in PAIS patients with phenotypes representing the full spectrum seen in this condition. In all cases the androgen receptor was found to be defective, suggesting that the mutation is the cause of the clinical phenotype. The Gln798Glu mutation is exceptional in that it did not cause an androgen-binding defect in our system, although the mutant receptor was defective in transactivation assays. This mutation may affect an aspect of binding not tested, or may be part of a functional subdomain of the ligand-binding domain involved in transactivation. Overall we found milder mutations to be associated with milder clinical phenotypes. There is also clear evidence that phenotype is not solely dependent on androgen receptor function. Some of the mutant receptors were able to respond to high doses of androgen in vitro, suggesting that patients carrying these mutations may be the best candidates for androgen therapy. One such mutation is Ile869Met. A patient carrying this mutation has virilized spontaneously at puberty, so in vivo evidence agrees with the experimental result. Thus a more complete understanding of the functional consequences of androgen receptor mutations may provide a more rational basis for gender assignment in PAIS.

Amino Acid Sequence↗
PubMed2000

2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring.

In utero and lactational exposure to a single maternal dose of 1 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Intraluminal androgen binding protein alters 3H-androgen uptake by rat epididymal tubules in vitro.

Previous experiments have shown that androgen binding protein (ABP) and androgens exist in high concentrations in the tissue and the lumen of the rat caput epididymis. The present experiments were performed to determine whether or not intraluminal APB affects tubule net uptake of androgens. Caput epididymal tubules were dissected into 2-cm segments, subjected to microperfusion into the tubule lumen, and incubated for 2.5 h in 35 degrees C minimum essential medium (MEM) containing 2.0 ng tritiated testosterone (3H-T) per ml. 14C-polytheylene glycol [PEG] was included as a contamination marker. In the first series of experiments, caput tubules were perfused with a control, artificial perfusion (MKB) containing no ABP or fresh rat rete testis fluid (RTF), which is known to contain ABP. Tubules incubated while containing RTF took up 138% of the tritiated androgens taken up by control tubules. In the second series of experiments, tubules were perfused with fresh caput epididymal lumen content, MKB alone, MKB containing either 5.0 ng purified rat ABP/microliters or 50 ng ABP/microliters. Tubules incubated while containing perfused MKB took up only 47% of the tritiated androgens taken up by tubules containing perfused native lumen content. Increasing intraluminal ABP concentrations in the MKB medium increased 3H-androgen uptake in a stepwise fashion. Intraluminal ABP at a concentration of 50 ng/microliters was associated with a 71% return of 3H-androgen uptake towards that amount of 3H-androgen taken up by tubules perfused with native lumen content. Intraluminal ABP enhances net androgen uptake by caput epididymal tubules from their surrounding medium in vitro.

Androgen-Binding Protein↗
PubMed2000

Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor.

The androgen insensitivity syndrome is a disorder caused by deficient function of the androgen receptor, characterized by varying degrees of undermasculinization in karyotypic males. We have identified four mutations in the androgen receptor gene, in the region encoding the DNA-binding domain of the protein. Two mutations, R607X and R615G, were found in patients with complete insensitivity to androgens, whereas the other two, S578T and A596T, were found in patients with partial insensitivity. The functional consequences of the three missense mutations were assayed in vitro after transient expression of the receptors in COS cells. All mutants showed normal androgen binding but abnormal abilities to stimulate transcription of an androgen-responsive reporter gene. R615G abolished transactivation whereas S578T and A596T were partially malfunctional. The function of A596T, but not of S578T, was normalized at high androgen concentrations in vitro, reflecting the in vivo situation. Thus, patients with specific mutations in the DNA-binding domain of the androgen receptor may benefit from androgen treatment.

Amino Acid Sequence↗
PubMed1992

Molecular analysis of the androgen receptor gene in 52 patients with complete or partial androgen insensitivity syndrome: a collaborative study.

In patients with androgen insensitivity syndrome (AIS), RFLP study of the androgen receptor gene made it possible to analyze whether deletions or mutations could be responsible for abnormalities in androgen responsiveness. We studied RFLPs of DNA from 25 46,XY patients with partial AIS (PAIS), defined as a concentration of androgen receptor in genital-skin fibroblasts less than 340 fmol/mg DNA, and DNA from 27 46,XY patients with complete AIS (CAIS) with no detectable androgen receptor site. DNA samples were digested with BamHI, EcoRI, HindIII and TaqI restriction enzymes and hybridized with three cDNA probes covering the three domains of the androgen receptor. When we had the maternal and an unaffected brother's DNA, we analyzed the two androgen receptor gene polymorphisms described, the HindIII and the exon 1 CAG repeat polymorphisms, in order to distinguish the two maternal X chromosomes, and to detect carriers of AIS. We did not find any large deletion among the 52 patients. We observed a heterozygous mother in 3 of 14 families studied with the HindIII polymorphism, and in 12 of 25 families using the exon 1 CAG repeat polymorphism. This study suggests that in AIS, abnormalities in androgen receptor response could be related to point mutations or microdeletions rather than to gross structural alterations of the androgen receptor gene. Furthermore, unless the point mutation has been described, exon 1 and HindIII polymorphism studies would enable the identification of carriers in 50% of families, and the prenatal diagnosis of AIS.

Androgens↗
PubMed1991

A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance.

Androgen resistance is associated with a wide range of quantitative and qualitative defects in the androgen receptor. However, fibroblast cultures from approximately 10% of patients with the clinical, endocrine, and genetic features characteristic of androgen resistance express normal quantities of apparently normal androgen receptor in cultured genital skin fibroblasts (receptor-positive androgen resistance). We have analyzed the androgen receptor gene of one patient (P321) with receptor-positive, complete testicular feminization and detected a single nucleotide substitution at nucleotide 2006 (G----C) within the second "zinc finger" of the DNA-binding domain that results in the conversion of the arginine residue at position 615 into a proline residue. Introduction of this mutation into the androgen receptor cDNA and transfection of the expression plasmid into eukaryotic cells lead to the synthesis of a receptor protein that displays normal binding kinetics but is inactive in functional assays of receptor activity. We conclude that substitution mutations in the DNA-binding domain of the androgen receptor are one cause of "receptor-positive" androgen resistance.

Androgen-Insensitivity Syndrome↗
PubMed2005

Microarray analysis of androgen-regulated gene expression in testis: the use of the androgen-binding protein (ABP)-transgenic mouse as a model.

BACKGROUND: Spermatogenesis is an androgen-dependent process, yet the molecular mechanisms of androgens' actions in testis are poorly understood. Transgenic mice overexpressing rat androgen-binding protein (ABP) in their testes have reduced levels of intratesticular androgens and, as a result, show a progressive impairment of spermatogenesis. We used this model to characterize changes in global gene expression in testis in response to reduced bioavailability of androgens. METHODS: Total RNA was extracted from testes of 30-day old transgenic and wild-type control mice, converted to cRNA, labeled with biotin, and hybridized to oligonucleotide microarrays. Microarray results were confirmed by real-time reverse transcription polymerase chain reaction. RESULTS: Three-hundred-eighty-one genes (3.05% of all transcripts represented on the chips) were up-regulated and 198 genes (1.59%) were down-regulated by at least a factor of 2 in the androgen-deficient animals compared to controls. Genes encoding membrane proteins, intracellular signaling molecules, enzymes, proteins participating in the immune response, and those involved in cytoskeleton organization were significantly overrepresented in the up-regulated group. Among the down-regulated transcripts, those coding for extracellular proteins were overrepresented most dramatically, followed by those related to proteolysis, cell adhesion, immune response, and growth factor, cytokine, and ion channel activities. Transcripts with the greatest potential impact on cellular activities included several transcription factors, intracellular signal transducers, secreted signaling molecules and enzymes, and various cell surface molecules. Major nodes in the up-regulated network were IL-6, AGT, MYC, and A2M, those in the down-regulated network were IL-2, -4, and -10, MAPK8, SOCS1, and CREB1. CONCLUSION: Microarray analysis followed by gene ontology profiling and connectivity analysis identified several functional groups of genes and individual genes responding to sustained reduction of androgen levels in the mouse testis. These include genes whose products function as transcription factors, cell surface molecules including ion channels, extra- and intracellular signaling molecules, and secreted enzymes with the potential of regulating cell-to-cell attachment. The transcription factors CREB1 (down-regulated) and MYC (up-regulated) may mediate the most important initial phases of the testicular response to reduced levels of androgens. These results suggest specific avenues for further research that will lead to a better understanding of how androgens regulate spermatogenesis.

Androgen-Binding Protein↗
PubMed1997

Immunohistochemical analysis of androgen effects on androgen receptor expression in developing Leydig and Sertoli cells.

Leydig and Sertoli cells are both targets of androgen action in the testis. Androgen exerts contrasting effects on the two cell types partially inhibiting steroidogenesis in adult Leydig cell and stimulating adult Sertoli cell functions required to support spermatogenesis. The developmental changes in the messenger RNA (mRNA) levels of androgen receptor (AR) also differ between Leydig and Sertoli cells, with Leydig cell AR mRNA being highest on day 35 postpartum, whereas Sertoli cell AR mRNA levels are highest on day 90. The purpose of the present study was to determine if the concentrations of AR in Leydig and Sertoli cells are differentially regulated during development using quantitative immunostaining. AR protein levels were measured in rat testes after hormonal treatments at three developmental stages: on days 21, 35, and 90 postpartum. At each age, five groups of animals were treated for 4 days with: 1) vehicle; 2) LHRH antagonist (NalGlu, 0.3 mg/kg BW.day) to suppress endogenous levels of androgen that accompany inhibition of LH and FSH secretion; 3) NalGlu + LH (0.2 mg/kg BW.day); 4) NalGlu + testosterone (T, at 7.5 mg/kg BW.day); and 5) NalGlu + MENT (a potent synthetic androgen, 7 alpha-methyl-19-nortestosterone, 0.7 mg/kg BW.day). AR protein was visualized by immunohistochemistry and measured by computer-assisted image analysis in Leydig and Sertoli cells using frozen sections of tests. After NalGlu treatment, AR levels in Leydig cells declined sharply to 42% and 31% of vehicle control (P < 0.01) in the 21 and 35 days postpartum age groups, respectively, but in 90-day-old rats there was no change. AR levels were partially maintained by exogenous LH, and completely maintained by exogenous androgen treatments in Leydig cells from 21- and 35-day-old rats, whereas in Leydig cells from 90-day-old rats, AR levels were unaffected in all treatment groups. In contrast, after NalGlu treatment, the AR concentration in Sertoli cells from 90-day-old rats were reduced to 32% of control (P < 0.01). Moreover, in Sertoli cells from 90-day-old rats, AR levels were partially maintained by LH and completely maintained by androgens. A similar trend was observed on day 35. On day 21, however, AR levels in immature Sertoli cells were unaffected in all treatment groups. These results indicate that androgen maximally stimulates AR levels in immature Leydig cells but is without significant effect in adult Leydig cells. In contrast, AR levels in Sertoli cells are more sensitive to androgen regulation in adult compared with immature animals. These findings indicate that there are distinct mechanisms controlling AR concentrations in Leydig and Sertoli cells during the development of the testis.

Androgens↗
PubMed1986

Complete androgen insensitivity syndrome characterized by increased concentration of a normal androgen receptor in genital skin fibroblasts.

Two siblings with the classical phenotype of complete androgen insensitivity syndrome (CAIS) and increased total cellular androgen receptor concentrations in genital skin fibroblasts (GSF) are described. Testosterone biosynthesis was normal, and there was no evidence of 5 alpha-reductase deficiency. Specific binding of [3H]dihydrotestosterone ([3H]DHT) in GSF was 7 SD above the mean value in normal fibroblast strains [maximum binding, 775 +/- 185 X 10(-18) mol/micrograms DNA (mean +/- SD)]. Binding at 40 C was stable, and the androgen-receptor complex dissociated at a normal rate (t1/2, 85 min). The androgen-receptor complex from GSF cytosol sedimented at 5-6S on sucrose density gradients in the presence of sodium molybdate. In a whole cell binding assay, the percentage of [3H]DHT that bound to a crude nuclear pellet was 60%. Preincubation of GSF with 2 nM [3H]DHT for 20 h before the standard 1-h whole cell binding assay produced a further augmentation in elevated total cellular androgen receptor concentrations. A new variant of CAIS is described which is characterized by an increased concentration of androgen receptors that appear to be quantitatively and qualitatively normal. Augmentation of the receptor by androgen suggests that the gene coding for the androgen receptor is intact and does not account for the androgen insensitivity.

Androgens↗
PubMed1992

Immunoreactive androgen receptor expression in subjects with androgen resistance.

Individuals with androgen resistance encompass a spectrum of phenotypic abnormalities ranging from complete testicular feminization to undervirilized men. Such subjects have been classified according to the hormone-binding characteristics in genital skin fibroblasts and on the basis of the mutation in the androgen receptor (AR) gene. Antibodies to the amino-terminal region of the human AR were used to develop an immunoblot assay for the comparison of androgen binding with the amount of AR expressed in genital skin fibroblasts. In controls and 4 androgen-resistant subjects with DNA-binding domain mutations, levels of immunoreactive AR correlated closely with androgen-binding capacity. In 15 androgen-resistant subjects with qualitatively abnormal AR, immunoreactive AR levels tended to be higher than predicted from the ligand-binding capacity. Discordance between immunoreactivity and androgen binding also occurred in fibroblasts from 3 other subjects. One carries a stop codon in the AR gene and produces a truncated AR that is immunoreactive but does not bind androgen. Two carry single point mutations in the hormone-binding domain and produce immunoreactive AR that is normal in size but does not bind androgen.

Androgens↗
PubMed1993

Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: application for diagnosis, genetic counseling, and therapy.

Recent studies indicate that mutations in the androgen receptor gene are associated with androgen insensitivity syndromes, a heterogeneous group of related disorders involving defective sexual differentiation in karyotypic males. In this report, we address the possibility of rapid mutational analysis of the androgen receptor gene for initial diagnosis, genetic counseling, and molecular subclassification of affected patients and their families. DNA from peripheral blood leukocytes of six patients from five families with various degrees of androgen insensitivity was studied. Exons 2 to 8 of the androgen receptor gene were analyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also studied to identify heterozygote carriers. Point mutations in the AR gene were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. Our data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome. Molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy, and can provide a basis for distinguishing heterozygous carriers in familial androgen resistance. The identification of carriers is of substantial clinical importance for genetic counseling.

Adolescent↗
PubMed2000

Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex.

Previous studies have shown that androgen up-regulates expression of the p21 (WAF1, CIP1, SDI1, CAP20) gene, which contains a canonical androgen response element (ARE) in its proximal promoter region. We undertook the current studies to determine whether elements in the p21 promoter other than the ARE mediate androgen action. We found that deletion of the ARE did not completely abolish the promoter responsiveness to androgen, suggesting that additional cis-regulatory elements within the p21 core promoter may also be involved in androgen responsiveness. The p21 core promoter is GC-rich and contains six binding sites for transcription factor Sp1. We determined whether one or more of these Sp1 sites mediate androgen responsiveness of the p21 promoter. To do so, we used a transient transfection assay with p21 promoter-luciferase reporter constructs. The reporter activity of a construct lacking the ARE but containing all six Sp1 sites was induced approximately 3-fold by androgen. Mutation of Sp1-3 nearly eliminated basal promoter activity as well as androgen responsiveness, whereas deletion of Sp1-1 and Sp1-2 sites and mutation of Sp1-4, Sp1-5, and Sp1-6 sites had relatively little effect. We also used the mammalian one-hybrid assay and coimmunoprecipitation assay to show that androgen receptor (AR) and transcription factor Sp1 interact with one another. The current studies suggest a model in which AR and transcription factor Sp1 not only bind to their respective consensus sites within the p21 promoter, but also complex with one another, thereby recruiting coactivators and general transcription factors and inducing p21 transcription.

Adenocarcinoma↗
PubMed1990

[A study of the androgenic activity of anti-androgen].

To investigate the androgenic activity of steroidal and nonsteroidal anti-androgens, the effect of several compounds on some parameters as an androgenic activity was measured in the ventral prostate (VP) and seminal vesicle gland (SV) of castrated male rats. Ornithine decarboxylase (ODC) activity, arginase activity, androgen receptor (AR) in cytosol and nucleus, histological examination and weight of accessory sex organs were used as parameters for androgenic activity. The ventral prostate weight was increased by the administration of not only steroidal anti-androgen, medroxyprogesterone (MPA), chlormadinone acetate (CMA) and cyproterone acetate (CPA), but also estradiol-17 beta(E2) and nonsteroidal anti-androgen, AA 560. However flutamide (Flu) failed to increase VP weight. In SV, the tendency to increase weight by the administration of these compounds was also observed. However, it was not obvious as in VP. It was proven by the measurement of the parameters that all tested compounds except Flu had an androgenic activity. It seems that the androgenic activity was caused by a different mechanism because the parameter response to the administrated compounds was not identical.

Androgen Antagonists↗
PubMed1998

Shortage of glutamine (CAG) homopolymeric repeats suppresses the expression of the androgen receptor in familial cases with complete androgen insensitivity syndrome.

The androgen receptor gene of two familial cases with complete androgen insensitivity syndrome was analyzed. The shortage of glutamine homopolymeric repeats (13 repeats) in the N-terminal domain of the androgen receptor of the patients was identified by DNA sequence analysis. In vitro transfection experiments with the patients' androgen receptor gene indicated that the expression of the androgen receptor in transfected COS-7 cells was decreased by 10% as compared to that of the wild type androgen receptor gene. The thermal stability of the 5 alpha-dihydrotestosterone-androgen receptor complex was also partially impaired. The capacity of the androgen receptor to activate target gene transcription was partially disturbed in a luciferase assay. The shortened glutamine homopolymeric repeats might therefore be related to the pathogenesis of complete androgen insensitivity syndrome.

Adult↗
PubMed2001

Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen.

The androgen receptor (AR) is highly expressed in androgen-dependent and recurrent prostate cancer (CaP) suggesting it has a role in the growth and progression of CaP. Previously proposed mechanisms for AR reactivation in recurrent CaP include altered growth factor signaling leading to protein phosphorylation and AR mutations that broaden ligand specificity. To further establish a role for AR in recurrent CaP, we compared several properties of AR in relation to the growth response to low levels of androgens in model systems of androgen-dependent and recurrent CaP. AR from all of the tumors and cell lines bound [3H]R1881 with similar high affinity (mean Kd, 0.12 nM). In the absence of androgen, AR in androgen-dependent LNCaP cells was unstable with a degradation half-time (t(1/2)) of 3 h at 37 degrees C. In contrast, AR was 2-4 times more stable in recurrent CWR22 tumors (t(1/2), >12 h) and CWR-R1 or LNCaP-C4-2 cell lines (t(1/2), 6-7 h) derived from recurrent prostate tumors. In the recurrent CWR22 tumor and its CWR-R1 cell line grown in the absence of androgen, AR immunostaining was entirely nuclear, whereas under the same conditions AR in LNCaP-C4-2 and LNCaP cells was predominantly nuclear but was also detected in the cytoplasm. High level expression, increased stability, and nuclear localization of AR in recurrent tumor cells were associated with an increased sensitivity to the growth-promoting effects of dihydrotestosterone in the femtomolar range. The concentration of dihydrotestosterone required for growth stimulation in CWR-R1 and LNCaP-C4-2 cells was four orders of magnitude lower than that required for androgen-dependent LNCaP cells. The results suggest that AR is transcriptionally active in recurrent CaP and can increase cell proliferation at the low circulating levels of androgen reported in castrated men.

Androgens↗
PubMed1992

Androgen resistance due to mutation of the androgen receptor.

The androgen receptor (AR) is a 'one-stop' signal transduction system that is the core of the intracellular androgen-response apparatus. It is an androgen-regulated, DNA-binding protein that regulates the expression of certain target genes, primarily at the transcriptional level. Mutations at the X-linked AR locus cause deficient or defective AR activity and, thereby, an extraordinarily wide spectrum of clinical androgen resistance. At one extreme, the affected 46,XY person is an infertile phenotypic female; at the other, he is a phenotypic male who may even be fertile, yet have gynecomastia or other focal signs of postpubertal subvirilization. We have identified 32 proven or putatively pathogenic alterations in the AR gene of 38 androgen-resistant families. This permits heterozygote detection and prenatal diagnosis whenever relevant. Most of the mutations affect the AR's androgen-binding domain, partly because our search has been targetted on those whose genital skin fibroblasts have impaired androgen-binding activities. The AR is a prototypic member of a subfamily that includes the receptors for progesterone, glucocorticoid, and mineralocorticoid. Observations that correlate AR genotype with clinical and receptor phenotypes of androgen resistance will help to generate a fine structure-function map of the AR and its close relatives. Constitutional variation in androgen sensitivity, that may be restricted to an organ (or organ system), could contribute to the pathogenesis of certain diseases whose sex ratio departs significantly from one.

Amino Acid Sequence↗