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At least 919 records · Page 51Linked to original sources
PubMed1975

Testicular androgen-binding protein (ABP): comparison of ABP in rabbit testis and epididymis with a similar androgen-binding protein (TeBG) in rabbit serum.

Testicular androgen-binding proteins (ABP) in rabbit testis, caput epididymis and efferent duct fluid (EDF) were compared to a similar androgen-binding protein TeBg) in rabbit serum. The affinity of these proteins for 5alpha-dihydrotesterone (DHT) at 0 degrees C (KaABP = 1.6 X 10(9) M-1 and KaTeBG = 1.9 X 10(9) M-1) and their steroid specificities were similar (DHT greater than androstanediol greater than progesterone and androstenedione). ABP and TeBG had also almost identical Stokes radii (42.8 +/- 1.2 and 43.9 +- 0.8 A, respectively), sedimentation coefficients (4.7 +/- 0.2 S and 4.4 +/- 0.2 S, respectively) and electrophoretic mobility (Rf = 0.4 in 6 1/2% polyacrylamide gels). Calculation of molecular weights from Stokes radii and sedimentation rates indicated a molecular weight of 74,000 (69,000-78,000) for TeBG and 76,000 (71,000-82,000) for ABP. The corresponding frictional ratios were 1.61 for TeBG and 1.55 for ABP assuming a partial specific volume (v) of 0.70 cm3/g. Polyacrylamide gel electrophoresis (PAGE) at different gel concentrations gave a mean molecular radius of 2.74 nm, also indicating a molecular weight of about 75,000 (v = 0.70 cm3/g. ABP and TeBG could not be separated by PAGE; however, partial separation of ABP and TeBG was achieved by isoelectric focusing and ion-exchange chromatography on DEAE-cellulose. TeBG focused at pH 5.4, whereas ABP formed a distinct peak of bound radioactivity at pH 4.7. Also by ionexchange chromatography, ABP in both testis and epididymal supernatants was shown to have an apparently higher surface charge than TeBG in rabbit serum. The concentration of ABP in efferent duct fluid (2 X 10(-7) M = 60 pmol/mg protien) was much higher than TeBG in male rabbit serum (5.2 X 10(-8) M = 0.7 pmol/mg protein). These findings ruled against the possibility that ABP in the testis and epididymis could have been derived directly from serum. It is concluded that ABP and TeBG are very similar if not identical proteins both serving as transport and carrier proteins in their respective compartments.

Androstenedione↗
PubMed2001

A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth.

The ligand-bound androgen receptor (AR) regulates target genes via a mechanism involving coregulators such as androgen receptor-associated 54 (ARA54). We investigated whether the interruption of the AR coregulator function could lead to down-regulation of AR activity. Using in vitro mutagenesis and a yeast two-hybrid screening assay, we have isolated a mutant ARA54 (mt-ARA54) carrying a point mutation at amino acid 472 changing a glutamic acid to lysine, which acts as a dominant-negative inhibitor of AR transactivation. In transient transfection assays of prostate cancer cell lines, the mt-ARA54 suppressed endogenous mutated AR-mediated and exogenous wild-type AR-mediated transactivation in LNCaP and PC-3 cells, respectively. In DU145 cells, the mt-ARA54 suppressed exogenous ARA54 but not other coregulators, such as ARA55-enhanced or SRC-1-enhanced AR transactivation. In the LNCaP cells stably transfected with the plasmids encoding the mt-ARA54 under the doxycycline inducible system, the overexpression of the mt-ARA54 inhibited cell growth and endogenous expression of prostate-specific antigen. Mammalian two-hybrid assays further demonstrated that the mt-ARA54 can disrupt the interaction between wild-type ARA54 molecules, suggesting that ARA54 dimerization or oligomerization may play an essential role in the enhancement of AR transactivation. Together, our results demonstrate that a dominant-negative AR coregulator can suppress AR transactivation and cell proliferation in prostate cancer cells. Further studies may provide a new therapeutic approach for blocking AR-mediated prostate cancer growth.

Blotting, Western↗
PubMed2005

A prospective analysis of the time to normalization of serum androgens following 6 months of androgen deprivation therapy in patients on a randomized phase III clinical trial using limited hormonal therapy.

PURPOSE: Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent therapy with gonadotropin-releasing hormone agonists (GnRH-A). While these are largely successful in decreasing testosterone (T) and dihydroxytestosterone (DHT) to castrate levels, discontinuation of such therapy often results in continued suppression of androgens for variable periods of time. We present the largest published series of patients evaluating the timing of T and DHT increase after cessation of GnRH therapy. MATERIALS AND METHODS: Serial T and DHT measurements were prospectively obtained every 3 months while on GnRH-A then monthly upon discontinuation of GnRH-A. Analysis of time from the second 3-month GnRH-A administration to T and DHT increase was undertaken. RESULTS: A total of 80 evaluable patients had a median time to T 50 ng/dl or greater of 12.9 weeks and a median time to T normalization (212 ng/dl or greater) of 16.6 weeks. Low baseline T was associated with a prolonged time to T 212 ng/dl or greater (p = 0.0086) and a similar trend was seen in patients older than 66 years (p = 0.08). There were 62 evaluable patients with a median of 14.9 weeks to DHT 150 pg/ml or greater. There was no association with Gleason score at diagnosis, on study prostate specific antigen, type of prior definitive therapy, or any prior hormonal therapy and time to increase in circulating androgens. CONCLUSIONS: After 6 months of GnRH-A therapy in these patients, DHT and T levels did not return to normal for a median of 14.9 and 16.6 weeks, respectively.

Aged↗
PubMed1993

Comparison of plasma androgen glucuronide levels after percutaneous or peroral androgen treatment in men: evidence for important splanchnic contribution to plasma 17 beta-hydroxyandrogen glucuronides.

To investigate whether glucuronides of 17 beta-hydroxyandrogens are formed mainly in peripheral tissues or in splanchnic tissues, we compared androstanediol (AD) glucuronide (ADG) and dihydrotestosterone (DHT) glucuronide (DHTG) levels as well as the ratios of glucuronides over free steroids after transcutaneous DHT gel administration to levels and ratios found after oral administration of testosterone undecanoate. Whereas DHT and AD plasma levels were much higher after transcutaneous DHT gel administration, ADG and DHTG levels as well as glucuronide/free androgen ratios were an order of a magnitude higher after oral TU. This indicates that 17 beta-hydroxyandrogen glucuronides cannot be considered specific metabolites of androgen target tissues and are formed to a large extent in the splanchnic circulation.

Administration, Cutaneous↗
PubMed1981

Metabolism of androgens by the active and inactive prostate gland, and the seasonal changes in systemic androgen levels in the grey squirrel (Sciurus carolinensis Gmelin).

The nuclear and cytoplasmic fractions derived from the actively secretory and inactive prostate of adult grey squirrels were incubated with radioactive testosterone and androstenedione. Testosterone was metabolized first to 5 alpha-dihydrotestosterone and then 5 alpha-androstane-3 alpha(beta), 17 beta-diols. Testosterone could also be transformed into androstenedione and then to androsterone, but no 5 alpha-dihydrotestosterone or diols could be synthesized from this pathway. Neither subcellular fraction of the inactive, non-secretory prostate could produce 5 alpha-androstane-3 alpha(beta), 17 beta-diols from testosterone either in the absence or presence of exogenous NADPH. The synthesis of androstenedione and 5 alpha-dihydrotestosterone by the nuclear and cytoplasmic fractions of the inactive gland were significantly increased compared to that in fractions of the active prostate. The increase was unaffected by exogenous NADPH. The concentration of androgen (testosterone plus 5 alpha-dihydrotestosterone) in systemic plasma was highest in December, the beginning of the breeding season. For the remainder of the breeding season, the androgen level was similar to that found in the non-breeding season. It is suggested that formation of 5 alpha-androstane-3 alpha(beta), 17 beta-diols was associated with the secretory activity of the prostate. The failure of the inactive prostate to synthesize these diols during sexual quiescence might be a means of ensuring the inactivity of the prostate.

Androstenedione↗
PubMed1983

Are fluorescein-conjugated androgens appropriate for a histochemical detection of prostatic androgen receptors?

Histochemical fluorescence techniques could be of great value in order to assay androgen receptors (AR), particularly in punch biopsies from human prostatic carcinoma (PCA). Therefore, prostatic tissue was examined for specific binding of fluorescein-labeled 5 alpha-dihydrotestosterone derivatives (FDHT) to AR. Using a 17 beta-fluoresceinated DHT derivative (17-FDHT), variable fluorescence was found in human and rat prostates at high 17-FDHT concentrations. This fluorescence could be blocked by unlabeled DHT in 11 and 73% of human and rat prostatic tissue, respectively. Control studies of receptor and organ specificity were conducted and showed that preheated slices from rat prostates displayed no decrease of fluorescent staining. No difference in fluorescence intensity could be seen between prostates from castrated and uncastrated rats. Unstained tissue slices frequently showed a considerable intensity of autofluorescence. An appreciable amount of fluorescence in both rat liver and spleen was found. From these results and various general methodical problems inherent in fluorescent receptor assays, we conclude that the fluorescence techniques described are inappropriate for demonstration of AR.

Androgens↗
PubMed1995

Synergistic effects of estrogen and androgen on the prostate: effects of estrogen on androgen- and estrogen-receptors, BrdU uptake, immunohistochemical study of AR, and responses to antiandrogens.

To investigate the synergistic effects of estradiol (E2) and testosterone (T) on prostate growth, castrated Wistar rats were treated with 1 mg/day of T or with 1 mg/day of T and 0.01 mg/day of E2 for 6 weeks. The weight of the prostate in T + E2-treated rats was significantly higher than that in T-treated and normal rats, parallel with the bromodeoxy-uridine (BrdU) labeling index (LI). Nuclear androgen receptor (AR) content in the T + E2 group was significantly higher than that in the T group. But they were lower than that in normal rats. And there were no significant differences between the groups in nuclear estrogen receptor (ER) content. Immunohistochemical studies with the AR antibody revealed positive staining in the prostatic epithelium and stromal cells in the normal, T-treated, and T + E2-treated animals. However, castration led to loss of staining. Response to steroidal antiandrogens was also determined. Antiandrogen treatment abrogated the increases in nuclear AR content and BrdU LI, and prevented immunohistochemical staining. These results suggest that AR and ER, which were measured in this study, were not indicators of prostatic proliferation. We further need to investigate other factors, including other types of receptors, growth factors involved in epithelial-stromal interaction, and so on.

Androgen Antagonists↗
PubMed1997

Induction of apoptosis and altered nuclear/cytoplasmic distribution of the androgen receptor and prostate-specific antigen by 1alpha,25-dihydroxyvitamin D3 in androgen-responsive LNCaP cells.

In addition to suppressing prostate cell growth, vitamin D also up-regulates the expression of androgen receptor (AR) and prostate-specific antigen (PSA). To study the mechanism involved in the control of these proteins, LNCaP cells were treated with 10 nM 1alpha,25-dihydroxyvitamin D3 and separated into cytosol and nuclear fractions. AR and PSA were analyzed by western blot analysis. A second approach involved incubating control and treated cells with [3H]R1881, fractionating the cells into the cytosolic and nuclear components, and quantifying the amount of radioactivity associated with the respective fractions. Alternatively, immunohistochemical assays were performed by staining cells with cognate antibodies for AR and PSA. Both biochemical and immunohistochemical analyses show proportionately greater increased presence of AR in the nucleus, accompanied by relatively reduced AR in the cytosol, following treatment of LNCaP cells with vitamin D3. Surprisingly, PSA was found to be present in the nuclear fraction in both control and treated cells. These results suggest that vitamin D3 promotes the translocation of AR from the cytosol to the nucleus. The presence of PSA in the nucleus of LNCaP cells raises the possibility of an autogenous mode of control of PSA gene expression.

Androgens↗
PubMed2001

Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor.

Whereas several apoptosis-related proteins have been linked to the antiapoptotic effects of Akt serine-threonine kinase, the search continues to explain the Akt signaling role in promoting cell survival via antiapoptotic effects. Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790. A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway results in the suppression of AR target genes, such as p21, and the decrease of androgen/AR-mediated apoptosis, which may involve the inhibition of interaction between AR and AR coregulators. Together, these findings provide a molecular basis for cross-talk between two signaling pathways at the level of Akt and AR-AR coregulators that may help us to better understand the roles of Akt in the androgen/AR-mediated apoptosis.

Amino Acid Substitution↗
PubMed2004

The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists.

The androgen receptor (AR) activates target gene expression in the presence of agonist ligands via the recruitment of transcriptional coactivators, but recent work shows that overexpression of the nuclear corepressors NCoR and SMRT attenuates this agonist-mediated AR activation. Here we demonstrate using NCoR siRNA and chromatin immunoprecipitation that endogenous NCoR is recruited to and represses the dihydrotestosterone (DHT)-liganded AR. Furthermore this study shows that NCoR and coactivators compete for AR in the presence of DHT. AR antagonists such as bicalutamide that are currently in use for prostate cancer treatment can also mediate NCoR recruitment, but mifepristone (RU486) at nanomolar concentrations is unique in its ability to markedly enhance the AR-NCoR interaction. The RU486-liganded AR interacted with a C-terminal fragment of NCoR, and this interaction was mediated by the two most C-terminal nuclear receptor interacting domains (RIDs) present in NCoR. Significantly, in addition to the AR ligand binding domain, the AR N terminus was also required for this interaction. Mutagenesis studies demonstrate that the N-terminal surface of the AR-mediating NCoR recruitment was distinct from tau5 and from the FXXLF motif that mediates agonist-induced N-C-terminal interaction. Taken together these data demonstrate that NCoR is a physiological regulator of the AR and reveal a new mechanism for AR antagonism that may be exploited for the development of more potent AR antagonists.

Androgen Receptor Antagonists↗
PubMed2006

Identification of putative androgen receptor interaction protein modules: cytoskeleton and endosomes modulate androgen receptor signaling in prostate cancer cells.

We have developed a novel androgen receptor (AR) expression system in the 293 human embryonic kidney cell line that recapitulates AR biochemical activity as a steroid hormone receptor in prostate cancer cells. We used this system to identify putative AR-binding proteins in the cytosolic and nuclear compartments of mammalian cells using a large scale co-immunoprecipitation strategy coupled to quantitative mass spectrometry. For example, the heat shock 70 and 90 chaperones, which are known regulators of steroid hormone receptor, were identified as AR-binding proteins. AR purification enriched for proteins involved in RNA processing, protein transport, and cytoskeletal organization, suggesting a functional link between AR and these protein modules in mammalian cells. For example, AR purification in the nuclear compartment led to the specific enrichment of alpha-actinin-4, clathrin heavy chain, and serine-threonine protein kinase C delta. Short interfering RNA knockdown studies and co-transcriptional reporter assays revealed that clathrin heavy chain possessed co-activator activity during AR-mediated transcription, whereas alpha-actinin-4 and protein kinase C delta displayed both co-activator and co-repressor activity during AR-mediated transcription that was dependent upon their relative expression levels. Lastly immunohistochemical staining of prostate tissue showed that alpha-actinin-4 levels decreased in the nucleus of high grade cancerous prostate samples, suggesting its possible deregulation in advanced prostate cancers as previously observed in late stage metastatic breast cancers. Taken together, these findings suggest AR binds to specific protein modules in mammalian cells and that these protein modules may provide a molecular framework for interrogating AR function in normal and cancerous prostate epithelial cells.

Androgen-Binding Protein↗
PubMed2000

Androgen insensitivity syndrome (AIS): emotional reactions of parents and adult patients to the clinical diagnosis of AIS and its confirmation by androgen receptor gene mutation analysis.

The emotional reactions of parents and adult patients on disclosure of the clinical diagnosis of androgen insensitivity syndrome (AIS) and its later confirmation by gene mutation analysis were assessed. A semistructured interview and three questionnaires were used. Parents came from 18 different families with a total of 20 children (15 complete AIS, 5 partial AIS), 19 raised as girls, 1 as a boy. Ten adult women with complete AIS came from six families. The short-term reaction upon the clinical diagnosis was in the majority of both parents and adult patients associated with shock, grief, anger, and shame and in the mothers and adult patients with guilt. Emotional reactions were more long-lasting in mothers and adult patients than in fathers. The confirmation by DNA analysis did not alter the actual feelings of both parents. Adolescents with AIS should be informed completely - but in a step-by-step way - about their condition, since adult patients indicated that they had suffered from being not at all or misinformed about AIS in their adolescence.

Adult↗
PubMed2001

A unique exonic splicing mutation in the human androgen receptor gene indicates a physiologic relevance of regular androgen receptor transcript variants.

In a patient with partial androgen insensitivity syndrome (AIS), we identified a single inherited presumably silent nucleotide variation (AGC -> AGT) in exon 8 (codon 888) of the AR gene. However, in the patient's genital skin fibroblasts, a considerably shortened transcript of 5.5 kb (normal: 10.5 kb) was detected, which misses a part of exon 8 and a prominent portion of the 3'-untranslated region. The translation product includes eight missense amino acids from codon 886 onward followed by a premature stop codon. As shown by in vitro expression analysis, the mutant protein lacks any residual function. However, reverse transcribed PCRs and sequence data indicate the existence of two additional splicing variants of 6.4 kb and 7.8-kb length both in patient and normal control genital skin fibroblasts. These splicing variants comprise the complete coding region but a shortened 3'-untranslated region. Thus, a distinct alternative pre-messenger RNA-processing event leading to two additional transcripts occurs generally in genital skin fibroblasts. In addition, this process partially prevents aberrant splicing in the patient and produces a small fraction of normal, functionally intact AR-protein that could explain the partial masculinization in this patient. This first report of an exonic splicing mutation in the AR-gene indicates a physiologic relevance of the regular AR-messenger RNA variants with shortened 3'-untranslated regions and their functional translation products in human genital development.

3' Untranslated Regions↗
PubMed2006

Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators.

We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.

Amino Acid Sequence↗
PubMed2000

c-Jun targets amino terminus of androgen receptor in regulating androgen-responsive transcription.

The human androgen receptor (hAR) is a member of the nuclear receptor superfamily and functions as a ligand-inducible transcription factor. We have previously proposed that c-Jun mediates the transcriptional activity of this receptor. The modular nature of hAR was used in this study to generate several fusions with the heterologous DNA-binding domain of the yeast transcription factor GAL4 in an attempt to identify the c-Jun-responsive domains within the receptor. Our results suggest that the target of c-Jun action is the amino terminus (AB region) of the receptor and that hAR amino acids 502-521 are critical for the c-Jun response. Additionally, amino acids 503-555 were shown to harbor an autonomous transactivation that is stimulated by c-Jun. Furthermore, we demonstrated that transcription intermediary factor-2 (TIF-2), a coactivator that acts on the activation function-2, stimulates the full-length hAR. These results suggest that c-Jun and TIF-2 can work together as coactivators on the hAR by targeting distinct portions of the receptor.

Androgens↗
PubMed1985

Interactions of an anti-androgen (cyproterone acetate) with the androgen receptor system and its biological action in the rat ventral prostate.

Male Wistar rats were castrated and implantated with testosterone-filled silastic depots (in vitro release rate: 60 micrograms/24 h) prior to treatment with 10 mg cyproterone acetate (CyAc) on day 1, and 5 mg on days 4, 7, 10 and 13. Animals were sacrificed on day 14. Control animals were treated identically, with the exception of CyAc administration. Blood was collected and the ventral prostates of 6-8 animals were pooled, homogenized and processed into cytosol and purified nuclei. Steroid determinations (CyAc, testosterone, 5 alpha-dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol)) were performed by RIA. Specifically bound DHT (charcoal resistant DHT = CR-DHT) represents DHT values (RIA) following treatment of cytosol or nuclear extract with dextran coated charcoal. The androgen receptor was determined in cytosol and nuclear extract by 'exchange assay' using [3H]methyltrienolone (MT) (18 h, 15 degrees C). The main results were: 1) The steroid levels in plasma (testosterone, DHT, 3 alpha-diol) were in the range of untreated adult animals and not significantly influenced by the CyAc treatment. Final CyAc levels were 305 +/- 58 nmol/l (mean +/- SD, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen Antagonists↗
PubMed1995

Biological implications of estrogen and androgen effects on androgen receptor and its mRNA levels in human uterine endometrium.

It has been shown that some effects of testosterone are different from those of its 5 alpha-reduced metabolite, dihydrotestosterone. Briefly, activities of testosterone might be related to cellular differentiation, whereas dihydrotestosterone acts on cellular proliferation. The number of testosterone binding sites in the uterine endometrium was increased by estradiol dipropionate, and this increase was down-regulated by testosterone cypionate. Dihydrotestosterone-specific binding sites in the endometrium were not modulated by estradiol dipropionate and testosterone cypionate. The dissociation constants of the binding sites for testosterone and dihydrotestosterone were not altered by these steroids. Estradiol dipropionate with or without testosterone cypionate induced androgen receptor mRNA expression in the endometrium. In conclusion, testosterone might predominantly affect cellular differentiation in the endometrium.

Adult↗