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PubMed1986

Regional variation of cytosol androgen receptors throughout the diseased human prostate gland.

The heterogeneous histology of the normal and diseased human prostate is well established. This study has investigated variations in cytosol androgen receptor (AR) content throughout the diseased gland to establish the most suitable sites to obtain tissue for AR assay. Only then can AR be investigated as a potential predictor of response to endocrine treatment. In a transverse slice of an enucleated prostate showing benign prostatic hyperplasia (BPH) AR levels in 1-g segments varied from 109 to 1,212 fmol/g tissue (mean 483 +/- 273; median 406), with no negative areas. Areas of higher receptor concentrations corresponded to the glandular regions of sections obtained from a slice taken in juxtaposition; areas of low receptor concentrations corresponded to the stromal regions. A significant correlation (P less than .02) was observed between AR concentration and the proportion of glandular components of each segment. Specimens were also obtained from each of three sites from 38 prostates; 45% of all specimens contained AR; however, distribution of receptor throughout the prostate was uneven. AR were significantly more likely to be measured in the peripheral zone (71% positive) than in periurethral tissue (39% positive) whilst only 24% of specimens taken from the limit of the resection possessed AR binding capacity. Similar distribution patterns were observed in both benign and malignant prostates, although 16% more specimens from carcinomatous prostates contained receptor than did those from benign glands; this difference was maintained at each site. In addition receptor levels were consistently lower in benign than in malignant specimens. It is therefore desirable to know the histological composition of specimens used for AR measurement.

Cytosol↗
PubMed1991

Morphological and functional similarities between cultured prostatic stromal cells and testicular peritubular myoid cells.

A number of androgen effects on epithelial cells may be mediated by androgen-regulated paracrine factors produced by underlying mesenchymal cells. In previous studies we demonstrated that prostatic stromal cells and testicular peritubular cells, derived from immature rats, produce mediators of androgen action with identical effects on Sertoli cells. In the present paper we further compared the morphological and functional characteristics of both mesenchymal cell types. Cultured prostatic stromal cells and testicular peritubular cells look identical under phase-contrast microscopy, share the ability to form tubular structures and "balls" when cocultured with Sertoli cells, and contain proteins immunoreactive with an antiserum against alpha-smooth muscle isoactin. Two-dimensional gel electrophoresis shows that the pattern of proteins produced by both cell types is nearly identical. Conditioned media from stromal and peritubular cells contain a factor that stimulates transferrin and cGMP production in Sertoli cells. The behavior of the active principle in the media from both cell types is comparable. On reverse-phase HPLC the elution profile of this factor is comparable for media from both cell types. In conclusion, these data point to a striking similarity in the morphological and functional characteristics of mesenchymal cells cultured from the prostate and testis.

Animals↗
PubMed1997

Defining a functional androgen responsive element in the 5' far upstream flanking region of the prostate-specific antigen gene.

Previously, an androgen responsive element (ARE or promoter ARE) was identified in the proximal promoter region of the prostate-specific antigen (PSA) gene. The proximal promoter fragment could mediate androgen induction of expression of a heterologous reporter gene in androgen receptor (AR)-less cells with exogenous AR in co-transfection assays. However, it exerted little androgen inducibility in androgen sensitive human prostate cells, LNCaP, which produce PSA mRNA and protein. In this study, we have identified a second functional ARE (or upstream ARE) approximately 4 kb upstream of the cap site of the PSA transcript. Interestingly, although the AREs are necessary for androgen induction, the DNA sequences surrounding the upstream ARE are also required for androgen induction by the PSA promoter in LNCaP cells. The results indicated that the upstream DNA sequences can cooperate with either ARE to mediate androgen induced gene expression in LNCaP cells.

Cell Nucleus↗
PubMed1998

Discovery of nonsteroidal androgens.

Nonsteroidal androgens have not been reported. During studies to identify affinity ligands for the androgen receptor in our laboratory, we synthesized several electrophilic nonsteroidal ligands for the androgen receptor and examined their receptor binding affinity and ability to stimulate receptor-mediated transcriptional activation. We found that three of these ligands (1) bound the androgen receptor with affinity similar to that of dihydrotestosterone (the endogenous ligand) and (2) mimicked the effects of dihydrotestosterone on receptor-mediated transcriptional activation (i.e., they were receptor agonists). These studies demonstrate that nonsteroidal ligands can be structurally modified to produce agonist activity. These ligands thus represent the first members of a novel class of androgens with potential therapeutic applications in male fertility and hormone replacement therapy.

Androgens↗
PubMed2001

Androgens regulate the mammalian homologues of invertebrate sex determination genes tra-2 and fox-1.

Androgens, like other steroid hormones, exert profound effects on cell growth and survival by modulating the expression of target genes. In vertebrates, androgens play a critical role downstream of the testis determination pathway, influencing the expression of sexually dimorphic traits. Among cells of the nervous system, motor neurons respond to trophic effects of androgen stimulation, with a subpopulation of spinal motor neurons exhibiting sexually dimorphic survival. To study the mechanisms of androgen action in these cells, we performed a subtractive screen for genes upregulated by androgen in a motor neuron cell line. We show androgen-inducible expression of two RNA-binding proteins that are the mammalian homologues of invertebrate sex determination genes. Androgens upregulate the expression of tra-2alpha, an enhancer of RNA splicing homologous to Drosophila tra-2, and promote redistribution of the protein from a diffuse to a speckled pattern within the nucleus. Similarly, androgens upregulate the expression of a novel gene homologous to Caenorhabditis elegans fox-1. These data indicate that androgens exert their effects, in part, by modulating the expression and function of genes involved in RNA processing, and identify homologues of invertebrate sex determination genes as androgen-responsive genes in mammals.

Amino Acid Sequence↗
PubMed2001

Recombinant expression and purification of human androgen receptor in a baculovirus system.

A full-length human androgen receptor (hAR) cDNA was used to produce recombinant baculovirus. Spodoptera frugiperda (Sf9) cells infected with this virus expressed protein with an N-terminal hexahistidine tag (His(6)-hAR) in soluble and insoluble forms. The soluble cytosolic His(6)-hAR demonstrated similar association and dissociation half-times for mibolerone, similar binding affinity for mibolerone, and similar steroid specificity as bona fide AR. Under native conditions, the soluble cytosolic His(6)-hAR was purified to apparent homogeneity in the presence of dihydrotestosterone, using metal ion affinity chromatography. The insoluble pellet fraction was solubilized with strong denaturant 6 M guanidine HCl, and His(6)-hAR was purified from it in the presence of 6 M guanidine HCl. Both the solubilized crude pellet fraction and the solubilized/purified His(6)-hAR could be renatured to bind mibolerone. The baculovirus system will therefore provide an efficient means for producing hAR for ligand-binding assays, as well as purifying hAR for detailed molecular analyses.

Animals↗
PubMed1998

Primary rat lacrimal cells undergo acinar-like morphogenesis on reconstituted basement membrane and express secretory component under androgen stimulation.

Single cells or small cell clusters, isolated from the rat lacrimal gland, were incubated on reconstituted basement membrane (matrigel) in a well-defined serum-free medium. During the first days of culture, cells reassociated and reorganized in structures resembling acini. These multicellular structures, maintained in culture for 2 weeks, consisted of well-polarized cuboidal cells surrounding a central lumen and exhibiting apically located microvilli. Myoepithelial cells were observed at the periphery of the acinar structures. Both in the native lacrimal and in the cultured aggregates, epithelial cells displayed strong immunoreactivity for cytokeratin 8, while myoepithelial cells were immunoreactive for vimentin and alpha-smooth muscle isoactin. These data indicate that the cultured aggregates closely mimic the in vivo architecture of lacrimal glands both by morphology and immunohistochemistry. We further demonstrated the presence of an intact androgen receptor and the ability of the cultured aggregates to respond to androgens with increased secretion of the secretory component. Comparable androgen responses were observed in lacrimal gland cultures of 5-week-old male and female rats. In conclusion, we report a morphologically and functionally differentiated culture system of primary rat lacrimal cells, in which androgen-regulated gene expression was observed. This culture model provides a unique experimental paradigm for studying the effects of hormones, cytokines, and growth factors on the morphogenesis, growth, and functional differentiation of lacrimal glands.

Actins↗
PubMed2000

Rainbow trout androgen receptor-alpha fails to distinguish between any of the natural androgens tested in transactivation assay, not just 11-ketotestosterone and testosterone.

We have recently isolated two androgen receptor cDNA clones from the rainbow trout testis. To investigate the functions of the rainbow trout androgen receptor-alpha (rtAR-alpha), we investigated the ligand binding ability and transcriptional activity of rtAR-alpha. Interestingly, in ligand-competition experiments, testosterone (T) (IC(50) 3 x 10(-9) M) competed with [(3)H]mibolerone binding for rtAR-alpha slightly more potently than the teleost fish-specific natural androgen 11-ketotestosterone (11KT) (IC(50) 8 x 10(-9) M), which is thought to be the functional spermatogenesis inducer. In contrast, T (EC(50) 5 x 10(-9) M) and 11KT (EC(50) 6 x 10(-9) M) showed similar efficiency upon cotransfection into EPC cells with a rtAR-alpha expression vector and an androgen-responsive element-based reporter gene. These results indicated that activation of rtAR-alpha does not distinguish between 11KT and T and suggested that a specific system, which is mediated only by 11KT, may exist in the rainbow trout.

Androgens↗
PubMed2000

A novel androgen-regulated gene, PMEPA1, located on chromosome 20q13 exhibits high level expression in prostate.

Biologic effects of androgen on target cells are mediated in part by transcriptional regulation of androgen-regulated genes (ARGs) by androgen receptor. Using serial analysis of gene expression (SAGE), we have identified a comprehensive repertoire of ARGs in LNCaP cells. One of the SAGE-derived tags exhibiting homology to an expressed sequence tag was maximally induced in response to synthetic androgen R1881 treatment. The open reading frame of the androgen-induced RNA (PMEPA1) was characterized as a 759-bp nucleotide sequence coding for a 252-amino-acid protein. The analysis of PMEPA1 protein sequence indicated the existence of a type Ib transmembrane domain between residues 9 and 25. Analysis of multiple-tissue Northern blots revealed the highest level of PMEPA1 expression in prostate tissue. PMEPA1 expression was predominately detected in glandular epithelial cells of prostate by in situ hybridization analysis. The expression of PMEPA1 in LNCaP cells was induced by androgen in a time- and dose-specific manner. Evaluation of PMEPA1 expression in androgen-dependent/independent tumors of the CWR22 xenograft model revealed that PMEPA1 was overexpressed in three of four androgen-independent tumor tissues. These observations define PMEPA1 as a novel androgen-regulated gene exhibiting abundant expression in prostate tissue. The increased expression of PMEPA1 in relapsed tumors of the CWR22 model suggests activation of androgen signaling in hormone refractory disease. PMEPA1, along with other highly androgen-induced prostate-specific genes, has potential to serve as an androgen signaling read-out biomarker in prostate tissue.

Androgens↗
PubMed1998

Effects of 17alpha-methyltestosterone on sexually dimorphic characters in the weakly discharging electric fish, Brienomyrus niger (Günther, 1866) (Mormyridae): electric organ discharge, ventral body wall indentation, and anal-Fin ray bone expansion.

Adult males of African weakly discharging electric fish (family: Mormyridae) are distinguished from juveniles and adult females by a dorsally directed indentation of the posterior ventral body wall and by massive bone expansion of the bases of a select number of anal-fin rays. These sexually dimorphic structures seem to facilitate the anal-fin reflex that is displayed during courtship when the male envelopes its anal fin around the female's to form a common spawning pouch. Expanded bone could provide additional surface for muscle attachment and thus assist in part with the courtship sequence. Based on the fact that the expression of the male sexually dimorphic electric organ discharge (EOD) is under androgen control, and that the female EOD can be masculinized through testosterone administration, we hypothesized that androgens should also drive anal-fin ray bone expansion in male mormyrids and equally effect male-like changes in treated juveniles and adult females. Exogenous androgen treatment (17alpha-methyltestosterone) of adult female Brienomyrus niger resulted in a male-like EOD, and male-typical structural transformations (body wall indentation and anal-fin ray bone expansion). Some of these changes were immediate and receded following hormone withdrawal (EOD), while others developed more slowly and were apparently permanent (indentation and bone formation). 17alpha-Methyltestosterone administration affected only those targets in females that are normally involved in the male's reproductive behavior, i.e., its courtship signal (EOD) and two morphological features (body-wall indentation and bone expansion). Rays of the dorsal or caudal fins were never affected.

Animals↗
PubMed2002

Methyl-testosterone induces male-typical ventilatory behavior in response to putative steroidal pheromones in female round gobies (Neogobius melanostomus).

Male round gobies (Neogobius melanostomus) transiently increase their rate of ventilation when exposed to nanomolar concentrations of three putative steroidal pheromones (etiocholanolone, ETIO; estrone, E1; estradiol-glucuronide, E2-3g), whereas females exhibit this response only to ETIO. In this study we implanted females with Silastic capsules that were empty (Blank) or filled with methyl-testosterone (MT) to determine whether androgen induces a male-typical pattern of ventilatory response. As with untreated females in our previous studies, Blank females increased ventilation only in response to ETIO. In contrast, MT females tested 2-3 weeks postimplant responded not only to ETIO, but also to E1 and E2-3g. These results provide the first demonstration of an androgen inducing a male-typical behavioral response to a steroidal pheromone in adult female fish. Together with our previous findings of sexually isomorphic sensory responses to steroid odorants, the present results also suggest that a central action of androgen is responsible for sexually dimorphic behavioral responses to putative pheromonal steroids in Neogobius.

Animals↗
PubMed1980

Androgen receptors in the diabetic rat.

Male rats rendered diabetic by IV streptozotocin (65 mg/kg body weight) were treated with exogenous insulin or testosterone. Charcoal-coated dextran and polyacrylemide gel electrophoresis techniques were employed in studying the characteristics of androgen (R1881) binding to prostate cytosol protein. In comparison with normal (N) rats, the replacement therapy of diabetic (D) animals with insulin (D + I) or testosterone (D + T) was able to restore epididymal weight (N = 0.40 +/- 0.04 g; D = 0.18 +/0 0.02 g; D + I = 0.42 +/- 0.05 g; D + T = 0.40 +/0 0.06 g) and total prostate weight (N = 0.24 +/- 0.02 g; D = 0.15 +/- 0.02 g; D + I = 0.24 +/- 0.05 g; D + T = 0.35 +/- 0.06 h). Testicular endogenous content of testosterone was restored after insulin treatment (N = 154 +/- 13 ng/testis; D = 41 +/- 5 ng/testis; D + I = 142 +/- 9 ng/testis), and significant improvements of serum testosterone levels were also achieved (N = 540 +/- 64 ng/100 ml; D = 238 +/- 37 ng/100 ml; D + I = 358 +/- 18 ng/100 ml). Prostate cytosol of streptozotocin-diabetic rats had strongly lowered capacity for 3H-R1881 binding compared with controls (94 and 12 fmol/mg protein, respectively). Testosterone treatment produced a 3.3-fold improvement of this lowered value, whereas the increment seen with insulin was less (1.5-fold). It is emphasized that some of the improvements caused by insulin replacement therapy in diabetic animals are due to the partial restoration of testosterone secretion. Thus, the combined actions of insulin and testosterone (instead of insulin alone) seem to be of major importance in the maintenance and regulation of accessory sex glands function.

Animals↗
PubMed1992

Soluble and nuclear type I and II androgen-binding sites in benign hyperplasia and cancer of the human prostate.

This paper presents an approach for the assessment of the androgen receptor (AR) status in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissues. Evaluation of AR was carried out in both soluble and nuclear fractions by a standard competition method, using tritiated mibolerone as radioligand. Based on our experience with breast and endometrial cancer, this approach focused on both type I (high affinity, low capacity) and type II (reduced affinity, higher capacity) binding sites, aiming mainly at establishing a putative "functional" receptor mechanism, i.e., the presence of type I AR in both cytosol and nucleus. Ancillary studies were carried out to exclude a potential overestimation of the AR content by interference with other steroid receptors, namely, progesterone (PgR) or glucocorticoid (GcR) receptors. Results showed that the interaction by PgR or GcR upon AR measurement was not relevant. The distribution of AR, namely the percent of positivity either in a single or in both cell compartments, was not significantly different in BPH (N = 32) or PCa (N = 24) tissues. For type I binding, the percent of positivity in both soluble and nuclear fractions (i.e., the "functional" AR status) was very close to that observed for other endocrine-related tumors, like breast cancer. Concentrations of type I AR appeared significantly higher in PCa than in BPH tissues; this was true for both soluble and nuclear fractions. In contrast, no significant difference was found in type II AR concentrations in either cell fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Differential sensitivity of hormone-responsive and unresponsive human prostate cancer cells (LNCaP) to tumor necrosis factor.

Two sublines, the hormone-sensitive LNCaP-FGC and the insensitive LNCaP-r (resistant) carcinoma cell lines, originating from the parental human prostatic carcinoma cell line LNCaP were tested for sensitivity to human tumor necrosis factor-alpha (TNF) using the MTT assay. Irrespective of the culture conditions, i.e., whether FGC cell growth was hormone stimulated or hormone deprived, a clear dose-related response was observed between the concentration of TNF (range: 5-5000 U/ml) in the culture medium and the percentage of growth inhibition. In medium containing androgen-depleted serum, in which FGC cells showed reduced proliferative activity, the percentage of inhibition by a concentration of 100 U/ml TNF was substantially higher than that found in hormone-stimulated cells (90% and 60%, respectively). In contrast to the FGC cells, the hormone-insensitive LNCaP-r cells were almost completely resistant to the action of TNF. Growth of the FGC cells was almost completely inhibited, whereas growth of the LNCaP-r cells was retarded with only 20% at dosages up to 5000 U/ml. This substantial difference in TNF responsiveness could not be ascribed to differences in TNF-binding capacity, as both the FGC and LNCaP-r cells were found to contain identical numbers of TNF-receptors (approximately 1000 sites/cell). A possible association between hormone responsiveness and TNF sensitivity is suggested for these LNCaP sublines.

Androgen Antagonists↗