Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the androgen receptor (AR) are thought to cause complete androgen insensitivity (CAIS) in 46,XY human subjects who have a female phenotype despite normal adult male concentrations of plasma testosterone. Assays of AR binding in cultured skin fibroblasts from subjects with CAIS show either an apparent absence of AR (AR-) or normal levels of AR (AR+) binding. In several subjects with CAIS, AR-, no gross AR mutation was detected by Southern blot analyses of genomic DNA and normal sized 10 kilobase mRNA was present on Northern blots of poly(A+) RNA from cultured genital skin fibroblasts. We have used the polymerase chain reaction to amplify individual exons within the human AR gene of subjects with CAIS and have identified point mutations in three subjects. In one AR- subject (R774C), amino acid 774 was changed from arginine (CGC) to cysteine (TGC), in another AR- subject (R831Q), arginine (CGA) was changed to glutamine (CAA) at position 831, and in an AR+ subject (V866M) a methionine (ATG) was substituted for valine (GTG) at position 866. Transfection of wild type and mutant AR cDNA clones into COS cells results in detection of AR protein by immunoblotting. AR ligand binding activity is absent in cells transfected with AR mutants R774C and R831Q, but present with AR mutant V866M. Androgen binding in cells transfected with AR mutant V866M has a 6-fold lower apparent binding affinity than that of wild-type AR. Transcriptional activation of the MMTV-CAT reporter gene was androgen dependent and specific and nearly maximal at physiological concentrations (10(-10) M) of androgen when wild-type AR was transfected into cells, whereas neither AR mutants R774C nor R831Q were able to stimulate CAT activity even at 10(-8) M androgen. AR mutant V866M was able to stimulate CAT activity but the androgen dose dependency was shifted toward pharmacological concentrations of steroid that exceed in vivo levels. The molecular basis of CAIS in humans exhibits genetic heterogeneity. Our study shows that some cases of CAIS are explained by an inability to form a functional AR-steroid complex and hence, the AR is unable to activate transcription of genes essential for male sex differentiation during fetal development.
Mol Endocrinol 1990 Dec
PMID:Functional characterization of naturally occurring mutant androgen receptors from subjects with complete androgen insensitivity. 208 79

Full-length rat and human androgen receptor (AR) cDNA clones were expressed in COS-7 and CV1 monkey kidney cells to analyze the AR protein using immunological and cotransfection techniques. The studies were aided by the development of two rabbit polyclonal antibodies, designated AR32 and AR52, directed against epitopes within the N-terminal region of AR. Each antibody recognizes native AR by sucrose gradient analysis and detects a 114-kilodalton protein in COS cells transfected with human or rat AR cDNA. Covalent binding of the synthetic androgen [3H]methyltrienolone (R1881) to the 114-kDa protein was saturable. The endogenous native AR was similarly 114 kDa on immunoblots of a human prostate adenocarcinoma cell line, LNCaP, and rat sex accessory gland extracts. AR was localized in nuclei of transfected COS cells and in LNCaP cells by immunocytochemical staining. Androgen induction of CAT activity was dose dependent in CV1 cells cotransfected with the AR expression vector and a reporter plasmid containing the mouse mammary tumor virus promoter linked to the chloramphenicol acetyltransferase gene. It is concluded that antipeptide antibodies are useful reagents in characterizing both native and denatured forms of the AR protein. The 114-kDa protein expressed transiently in cultured cells represents the full-length AR protein, has a molecular size equivalent to that of endogenous AR, and mediates androgen-dependent transcriptional activation in CV1 cells.
Mol Endocrinol 1990 Sep
PMID:Expression of recombinant androgen receptor in cultured mammalian cells. 217 2

We have used monoclonal antibodies against the estrogen (E), progestin (P) and androgen (A) receptors (R) to study receptor localization and regulation in the seminal vesicles of rhesus monkeys under different hormonal conditions. The antibodies caused substantial shifts of the appropriately labeled receptors on sucrose gradients. ER levels were lower in intact males than in immature, castrate, and estrogen-treated castrates. With immunocytochemistry, ER were detectable only in stromal and smooth muscle cells, not the epithelium. The number of ER-positive stromal cells was significantly lower in intact males than in immature, castrate, and estrogen-treated castrates, and low in a DHT-treated castrate animal. Androgen receptors were localized in epithelial as well as stromal and smooth muscle cells, and the number of AR-positive stromal cells was highest in intact adults and lowest in castrated and immature animals. Estrogen treatment at the time of castration induced PR in the ER-positive stromal cells, prevented a decline in the number of AR-positive stromal cells, and caused stromal hypertrophy. In summary, in the seminal vesicle, as in the prostate, ER is restricted to the fibromuscular stroma, is suppressed by androgens, and can mediate induction of PR on estrogen treatment. Androgen receptors are present in epithelial as well as stromal and smooth muscle cells, but variations in hormonal state appear to affect regulation of AR more in the stroma than the epithelium.
J Steroid Biochem Mol Biol 1990 Sep
PMID:Localization and regulation of estrogen, progestin and androgen receptors in the seminal vesicle of the rhesus monkey. 224 43

Androgen action is largely determined by the formation of dihydrotestosterone in target tissues. In women, androstenedione is the major precursor of dihydrotestosterone production in female genital skin. The present study was initiated to determine whether androstenedione is converted to dihydrotestosterone primarily via testosterone or 5 alpha-androstane-3,17-dione (5 alpha-androstanedione), and to examine the pathway of androstenedione metabolism in genital skin. Genital skin was obtained from 9 normal premenopausal women and 2 normal men. Each tissue was incubated with [3H]androstenedione in RPMI-1640 medium for 1 h at 37 degrees C in 95% O2/5% CO2. The metabolites were separated and purified by paper partition and thin-layer chromatography. The conversions of androstenedione to 5 alpha-androstanedione and to androsterone were similar (10.45 +/- 1.46 and 11.04 +/- 2.04%/200 mg tissue), and were approx. 12, 8 and 23 times higher than the conversion of androstenedione to testosterone, dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol, respectively. The male samples showed a similar pattern of metabolism. These data indicate that 5 alpha-androstanedione is the most important intermediate in the conversion of androstenedione to dihydrotestosterone. The data also confirm the importance of 5 alpha-reductase activity over that of 17 beta-hydroxysteroid oxidoreductase activity in the expression of androgen action in women.
J Steroid Biochem Mol Biol 1990 Sep
PMID:Androstenedione is an important precursor of dihydrotestosterone in the genital skin of women and is metabolized via 5 alpha-androstanedione. 224 46

The hepatic tissue of the male rat exhibits a gradual decline and ultimate loss in androgen responsiveness during in vivo aging. Appearance of the age-associated androgen insensitivity can be delayed by dietary calorie restriction, an effective means for life-span extension. The androgen receptor mRNA is detectable in the liver only in its androgen-responsive state. Pubertal appearance of hepatic androgen sensitivity is remarkably correlated with the concomitant appearance of a cytoplasmic androgen binding (CAB) protein. Androgen resistance during senescence is associated with the loss of hepatic CAB activity as well. We are investigating the molecular basis for the temporal modulation of this hormone sensitivity through studies on the differential expression of two androgen-responsive marker genes. These are the androgen-repressible SMP-2, and the androgen-inducible alpha 2u-globulin. Androgen resistance of hepatocytes during aging results in repression of the alpha 2u-globulin gene, and derepression of the SMP-2 gene. The structural organizations for both of these genes have been characterized. The role of nuclear transcription factors (androgen receptor and any other transacting factor(s) which may be involved) in the coordinate regulation of alpha 2u-globulin and SMP-2 during aging and nutritional manipulation is being explored to establish the molecular mechanism of andropause in the liver.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Changes in hepatic androgen sensitivity and gene expression during aging. 225 47

Binding of androgens to adipocytes has previously been evaluated using cytosol fractions without taking into account nuclear binding, although the latter is suggested to be close to the physiological site of action. In the present study, performed in differentiated fat pad adipose precursor cells, we describe a simple, reliable and reproducible androgen binding assay in a system with intact cells. Tritiated and unlabeled methyltrienolone (R1881) were used to define specific and unspecific androgen binding. Triamcinolone acetonide was added to prevent the binding of R1881 to other types of receptors. Differentiated adipose precursor cells contain a homogeneous class of high affinity androgen binding sites, and binding is saturable and reversible. Binding apparently occurs at one site, with a Kd in the range of physiological androgen concentration (about 4 nM). Competition studies indicate that the receptor is specific for R1881, testosterone and dihydrotestosterone, which have approximately the same affinity, while progesterone, estradiol and dexamethasone show much lower affinity. Androgen binding was markedly enhanced after cellular exposure to R1881 and testosterone but not dihydrotestosterone, and this increase was dependent on protein synthesis, suggesting the formation of new receptors by these androgens. In conclusion, fully differentiated adipocytes contain a specific, high affinity receptor, the density of which is dependent on androgens.
J Steroid Biochem Mol Biol 1990 Nov 30
PMID:Up-regulation of androgen receptor binding in male rat fat pad adipose precursor cells exposed to testosterone: study in a whole cell assay system. 227 39

A current hypothesis suggests that androgen administration prior to chemotherapy (androgen priming) may potentiate tumor cytotoxicity in prostate cancer. The Dunning R3327G rat prostatic tumor model was used to test this concept experimentally. Control groups without priming included (1) intact untreated, (2) castrate alone and (3) castrate+ chemotherapy (cyclophosphamide, 30 mg/kg/day for 2 days with repeat cycle in 25 days- CTX). Two experimental groups received androgens, one before and one after chemotherapy. Treatment effect was monitored by quantitating tumor volume and animal survival. Control groups receiving castration and chemotherapy had a retardation of tumor growth and a prolongation of survival when compared to untreated animals. Androgen priming before but not after chemotherapy enhanced the degree of tumor suppression. With the androgen-priming protocol, all androgen-primed tumors had regressed, 3/6 tumors had disappeared and 3 were only palpable. At the same time point, tumors in all the other groups were actively growing and had volumes greater than the initial values (P less than 0.01). Median survival was significantly prolonged in primed animals 191 vs 40 days for untreated animals and 150 days for the nonprimed castration + chemotherapy animals (P less than 0.02). These findings have been repeated with several replicate experiments. These observations confirm the hypothesis that androgen priming can potentiate chemotherapy in an experimental system.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Androgen-primed chemotherapy-experimental confirmation of efficacy. 228 85

FSH beta, as well as LH beta, and alpha-subunit mRNA levels were examined in the pituitary glands of male rats after sex steroid replacement at various times (7, 28, or 90 days) after orchiectomy. Testosterone propionate, dihydrotestosterone propionate, or 17 beta-estradiol benzoate (E) were administered daily for 7 days before killing, to assess the role of different gonadal steroids on gonadotropin subunit mRNA levels. Subunit mRNAs were determined by blot hybridization using rat FSH beta genomic DNA, and alpha and LH beta cDNAs. At all time points, alpha and LH beta mRNAs increased after gonadectomy and fell toward normal levels with either androgen or estrogen replacement. FSH beta mRNA levels increased variably postcastration: 4-fold at 7 days, 2-fold at 28 days, and 4- to 5-fold at 90 days. Although E replacement uniformly suppressed FSH beta mRNAs, neither testosterone propionate nor dihydrotestosterone propionate administration suppressed FSH beta mRNA levels at any time point after orchiectomy. These data demonstrate that there is a relative lack of negative regulation of FSH beta mRNA levels by androgens in a paradigm in which E administration results in marked negative regulation of FSH beta mRNA levels. Thus, in the male rat, estrogens negatively regulate all three gonadotropin subunit mRNA levels while androgens negative regulate LH beta and alpha-subunit but fail to suppress FSH beta mRNAs.
Mol Endocrinol 1988 Jun
PMID:Selective failure of androgens to regulate follicle stimulating hormone beta messenger ribonucleic acid levels in the male rat. 245 24

Androgens regulate growth of the rat ventral prostate gland. In a search for possible mediators of androgen stimulated growth we have studied c-myc proto-oncogene expression in ventral prostate after androgen withdrawal and replacement. Steady state levels of c-myc mRNA were determined by Northern hybridization and compared with mRNA levels for prostatein, the major androgen dependent protein of ventral prostate. C-myc mRNA in ventral prostate increased nearly 4-fold within 1 day and 6- to 7-fold within 2 days after castration. Administration of androgen at the time of castration prevented this increase in c-myc mRNA levels. Androgen treatment of 4-day castrate rats caused c-myc mRNA levels to decrease within 4 h. Cycloheximide increased c-myc mRNA severalfold within 2 h. The net increase in c-myc mRNA after cycloheximide treatment was greater in the castrate than in the noncastrate or in androgen-treated castrate rats. These results suggest that androgen may influence both transcription and turnover of c-myc mRNA. Prostatein C3 mRNA decreased rapidly after castration and increased after androgen treatment of the castrate but was only slightly influenced by cycloheximide. Steady state levels of c-myc mRNA were higher in the 10-day-old rat and decreased with age while prostatein C3 mRNA increased with age. In situ hybridization demonstrated that both c-myc and prostatein mRNAs are expressed in the epithelial cells of ventral prostate acinar glands. These data indicate that androgens regulate the expression of c-myc in the ventral prostate.
Mol Endocrinol 1987 Dec
PMID:Androgen regulation of c-myc messenger ribonucleic acid levels in rat ventral prostate. 248 17

Transcription of the mouse mammary tumor virus DNA is known to be induced by several steroid hormones. Using chimeric MMTV plasmids containing mutations within the hormone regulatory element, we have previously studied the regions required for the glucocorticoid response in mouse fibroblasts. Here we report the characterization of elements essential for the stimulation by progestins and androgens as compared with glucocorticoids. The same set of mutant plasmids was transfected into the human mammary tumor cell line T47D, and the specific transcripts were analyzed by an S1 nuclease protection assay. Androgen-mediated stimulation, although weak, showed an extended sensitivity to mutations, with a slight preference for the proximal region. The results with progestin suggest that sequences within all the described sites protected by the receptor in vitro are required and that the promoter-proximal region (-128 to -78 from the RNA start site) is more important than the distal one (-190 to -160). Moreover, a binding site for nuclear factor I was not required for the progestin response, whereas it was required for glucocorticoids. Thus, the various steroid receptors play a role in the differential regulation of mouse mammary tumor virus transcription by recognizing distinct sequence differences in the hormone regulatory element and interacting with different factors bound to the promoter.
Mol Cell Biol 1989 Sep
PMID:Mutations in the hormone regulatory element of mouse mammary tumor virus differentially affect the response to progestins, androgens, and glucocorticoids. 255 Aug 9


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