Prolonged influence of a neonatal cyproterone acetate treatment on renal androgen binding in mice

1988 ◽  
Vol 119 (2) ◽  
pp. 263-268
Author(s):  
G. Veyssiére ◽  
Ch. Gallon ◽  
M. Berger ◽  
Ch. Jean-Faucher ◽  
M. de Turckheim ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Cyproterone Acetate ◽  
Single Injection ◽  
Adult Males ◽  
Male Mice ◽  
Testosterone Levels ◽  
Low Levels ◽  
Androgen Binding

Abstract. To determine whether neonatal endogenous androgens influence adult renal androgen binding, newborn male mice were injected from 1 to 10 days of age with cyproterone acetate and newborn females with testosterone from 1 to 10 days and from 20 to 40 days of age. In controls, at adulthood, the total cellular androgen receptor content was significantly higher in males (1700 200 receptors per cell) than in females (1060 ± 50) and, as expected, the nuclear receptor content was 12-fold higher in males. While the total number of receptors (1650 ± 220 per cell) was unchanged in adult males neonatally treated with cyproterone acetate, their distribution between cytosol and nucleus was similar to that in control females despite normal circulating and renal testosterone levels. The nuclear receptors represented 50, 7 and 11% of the total receptors in control males, control females and cyproterone acetate-treated males, respectively. The very low levels of nuclear receptors present in the kidney of cyproterone acetate-treated males probably explain the decreased sensitivity of this organ to testosterone. The nuclear receptor accumulation measured in adult animals after a single injection of testosterone did not seem to be affected by neonatal hormonal manipulations.

Sex difference in the cytosolic and nuclear distribution of androgen receptor in mouse submandibular gland

1986 ◽  
Vol 108 (2) ◽  
pp. 267-273 ◽  
Author(s):  
S. Kyakumoto ◽  
R. Kurokawa ◽  
Y. Ohara-Nemoto ◽  
M. Ota
Keyword(s):  
Androgen Receptor ◽  
Nuclear Receptors ◽  
Binding Sites ◽  
Androgen Receptors ◽  
Dissociation Constants ◽  
Scatchard Analysis ◽  
Male And Female ◽  
Short Period ◽  
Almost All ◽  
Androgen Binding

ABSTRACT Cytosol and nuclear androgen receptors in submandibular glands of male and female mice were measured by an exchange assay at 0 °C. The binding of [3H]methyltrienolone to cytosol receptors in females was mostly saturated within a short period of incubation (3 h), whereas the saturation was much slower in males; suggesting that almost all of the cytosol receptors were unoccupied in females and the receptors were partially occupied in males. Nuclear receptors were extracted with pyridoxal 5′-phosphate (5 mmol/l) from nuclear fractions with 93–95% efficiency. The exchange of the bound steroids occurred by 24–48 h at 0 °C, suggesting that most of the nuclear androgen receptor was occupied. The binding was low at higher temperatures, probably due to inactivation of the receptor. Scatchard analysis showed that the apparent dissociation constants of cytosol and nuclear receptors were similar (0·8 and 0·9 nmol/l respectively) in both sexes. On the other hand, the number of androgen-binding sites in the nucleus was much higher in males than in females (1052 fmol/mg DNA and 32 fmol/mg DNA respectively), while the number in the cytosol was higher in females than in males (512 fmol/mg DNA and 368 fmol/mg DNA respectively). These observations show that androgen receptors exist mainly (74%) in the nuclei of males, while they exist mostly (94%) in the cytosol of females. J. Endocr. (1986) 108, 267–273

scholarly journals SUN-LB138 Dynamic Structural Model of Testosterone Entry Into the Unliganded Androgen Receptor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Irina Krylova ◽  
Fred J Schaufele ◽  
Christophe Guilbert
Keyword(s):  
Amino Acids ◽  
Androgen Receptor ◽  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Binding Pocket ◽  
Binding Domain ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Crystallographic Structures

Abstract Background: Crystallographic structures of nuclear receptor ligand binding domains provide a static model of a receptor stably wrapped around an internalized ligand. Understanding the dynamics of a receptor at different stages of ligand binding has been hampered by the paucity of crystal structures for unliganded nuclear receptors. Molecular dynamic models have been constructed for some nuclear receptors to fill that void. Methods: The molecular simulation docking program MORDOR (MOlecular Recognition with a Driven dynamics OptimizeR)(1) was used to study the structural dynamics of the androgen receptor ligand binding domain (AR LBD) modeled from the static structure of the AR LBD bound to testosterone (T) (PDB ID: 2AM9). The goals of the study were to understand a) the dynamic interaction of the T in its binding pocket, b) AR LBD structural flexibilities that permit T entry/exit from the binding pocket and c) a model of the unliganded AR LBD. Results: Modeling AR LBD structure flexibility over time revealed possible alternative dynamic structures, including those without ligand, overlaid against the canonical nuclear receptor structure. The model dynamically tracks the structural changes as a ligand enters into the ligand binding domain and nestles into the ligand binding pocket. The model predicted the appearance of alpha helices within the AR LBD that transiently fold/unfold during the ligand entry phases. Once in the pocket, the ligand itself remains very dynamic in a still flexible pocket. The model predicted also AR LBD amino acids that sequentially interact with the ligand during its dynamic entry into the AR LBD. Intriguingly, those AR amino acids include those mutated in castration-resistant prostate tumors that continue to grow during androgen suppression therapy. Functional studies showed those mutant ARs had a primary consequence of enhancing response to lower level T, and other androgens, consistent with their role in creating a higher affinity AR that can scavenge low-level androgens in an androgen-suppressed patient. Conclusions: The molecular model of T binding to the AR LBD suggests a degree of structural dynamism not evident in the crystallographic structures commonly associated with nuclear receptors. Some AR mutations activating prostate tumor growth may do so by impacting androgen entry/exit, rather than by altering androgen fit into the ligand binding pocket. Reference: (1) Guilbert C, James TL (2008) J Chem Inf Model. 2008 48(6): 1257-1268. doi: 10.1021/ci8000327

scholarly journals Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

2004 ◽  
Vol 379 (3) ◽  
pp. 731-738 ◽  
Author(s):  
Cor A. BERREVOETS ◽  
Arzu UMAR ◽  
Jan TRAPMAN ◽  
Albert O. BRINKMANN
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Conformational Change ◽  
Nuclear Receptor ◽  
Cyproterone Acetate ◽  
Transcriptional Activity ◽  
Differential Modulation ◽  
Partial Agonists ◽  
Receptor Action

Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)- and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonist-bound AR has a preference for N-CoR. The AR mutation T877A (Thr877→Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of N-CoR. The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

scholarly journals Development of Peptide Antagonists for the Androgen Receptor Using Combinatorial Peptide Phage Display

2005 ◽  
Vol 19 (10) ◽  
pp. 2478-2490 ◽  
Author(s):  
Ching-yi Chang ◽  
Jennifer Abdo ◽  
Tanya Hartney ◽  
Donald P. McDonnell
Keyword(s):  
Androgen Receptor ◽  
Phage Display ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Binding Pocket ◽  
Orphan Nuclear Receptors ◽  
Nuclear Receptor Coactivator ◽  
Pharmacological Significance ◽  
Peptide Phage Display

Abstract Under the auspices of the Nuclear Receptor Signaling Atlas (NURSA) , we have undertaken to evaluate the feasibility of targeting nuclear receptor-coactivator surfaces for new drug discovery. The underlying objective of this approach is to provide the research community with reagents that can be used to modulate the transcriptional activity of nuclear receptors. Using combinatorial peptide phage display, we have been able to develop peptide antagonists that target specific nuclear receptor (NR)-coactivator binding surfaces. It can be appreciated that reagents of this nature will be of use in the study of orphan nuclear receptors for whom classical ligands have not yet been identified. In addition, because the interaction of coactivators with the receptor is an obligate step for NR transcriptional activity, it is anticipated that peptides that block these interactions will enable the definition of the biological and pharmacological significance of individual NR-coactivator interactions. In this report, we describe the use of this approach to develop antagonists of the androgen receptor by targeting its coactivator-binding pocket and their use to study the coactivator-binding surface of this receptor. Based on our findings, we believe that molecules that function by disrupting the androgen receptor-cofactor interactions will have use in the treatment of prostate cancer.

scholarly journals Passive Smoking Has the Same Negative Effects on Reproductive Hormones in Adult Males as Active Smoking

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 30s-30s
Author(s):  
I. Bassey ◽  
U.O. Akpan ◽  
I.K.P. Isong ◽  
A.E. Udoh
Keyword(s):  
Vitamin E ◽  
Serum Levels ◽  
Reproductive Hormones ◽  
Active Smoking ◽  
Adult Males ◽  
Negative Effects ◽  
Testosterone Levels ◽  
The Mean ◽  
Low Levels ◽  
Level Of Significance

Background: Smoking is an extremely lethal act and is associated with many illnesses. Lately, major concerns that passive smokers face the same health risks if not higher as active smokers have been raised. Some studies have shown that active smoking is associated with low levels of vitamins and testosterone. Are these facts also valid in passive smokers? Aim: The aim of this research was to estimate the levels of cotinine, testosterone, follicle stimulating (FSH) and luteinizing hormone (LH), prolactin, vitamin E and catalase and compare these parameters in male active and passive smokers. Methods: Serum levels of cotinine, testosterone, FSH, LH, prolactin and vitamin E and catalase were estimated in 60 cigarette smokers, 60 passive smokers and 60 nonsmokers recruited from Calabar metropolis. The hormones were assayed using ELISA and vitamin E using HPLC. Sociodemographic and anthropometric indices were obtained and data analyzed using PAWstatistic 18. The level of significance was set at P < 0.05. Results: Cotinine levels were significantly ( P = 0.0001) higher in active smokers than in passive smokers and controls. Vitamin E and testosterone was significantly lower in active ( P = 0.003 and P = 0.0001) and passive smokers ( P = 0.0001 and P = 0.0001) when compared with nonsmokers. The mean catalase level of active smokers only was significantly ( P = 0.043) lower than that of the controls. The FSH of the active smokers were significantly higher ( P = 0.034) than those of the controls while the passive smokers had the highest LH values ( P = 0.0001). However, there were no significant variations in the prolactin levels among the three groups. About 3% of the active smokers had testosterone levels less than 3 ng/mL (hypogonadic) but none of the passive smokers or controls had testosterone levels less than 3 ng/mL. Conclusion: Passive and active smoking depletes vitamins E and lowers testosterone levels. This may be a contributing factor to male infertility both groups of smokers.

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

2004 ◽  
Vol 11 (1) ◽  
pp. 117-130 ◽  
Author(s):  
S M Powell ◽  
V Christiaens ◽  
D Voulgaraki ◽  
J Waxman ◽  
F Claessens ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Point Mutations ◽  
Steroid Receptor ◽  
Activation Function ◽  
Steroid Receptor Coactivator ◽  
Basal Transcriptional Machinery ◽  
Independent States

The androgen receptor (AR) is a member of the nuclear receptor superfamily. These ligand-activated transcription factors usually contain two activation functions, a ligand-independent activation function 1(AF1) in the divergent N-terminal domain and a ligand-dependent AF2 in the more conserved C-terminal ligand-binding domain. To promote transcription from target promoters, DNA-bound nuclear receptors recruit coactivator proteins that promote transcription by modifying histones within nucleosomes, resulting in altered topology of chromatin to allow access of the basal transcriptional machinery, or stabilising the pre-initiation complex. It is well known that most coactivators interact with AF2 of many nuclear receptors via conserved, helical LxxLL motifs (where L is leucine and x is any amino acid). The AF2 of the AR is very weak, but we were able to demonstrate that its intrinsic ligand-dependent activity is potentiated by steroid receptor coactivator-1 (SRC1) and that this region interacts with coactivators via LxxLL motifs. However, a mutant SRC1 coactivator with no functional LxxLL motifs was still able to potentiate AR activity. We found that SRC1 can also be recruited to (and increase activity of) AF1 of the AR via a conserved, glutamine-rich region. Point mutations within this region abolish SRC1 interaction with AF1 and also abolish or severely impair its ability to potentiate AR activity on all promoters tested. Thus the AR interacts with SRC1 via two different regions and the AF1 interaction is functionally the more important, although the contribution of the two interactions varies in a promoter-dependent fashion. SRC1 then potentiates receptor activity via recruitment of CBP/p300, a histone acetyltranferase. This is important in the context of prostate cancer as SRC1 and other coactivators including CBP are coexpressed with AR in the luminal epithelial cells of the prostate, where over 90% of prostate tumours arise. There is a need for effective second-line prostate cancer therapy aimed at blocking the AR pathway when anti-androgen therapy has failed. Since there is growing evidence that nuclear receptor cofactors may be implicated in the progression of hormone-dependent tumours to hormone-independent states, novel targets could include the interaction of AR with coactivator proteins. We suggest that the N-terminal interaction would be a more specific and effective target in the case of prostate cancer than the LxxLL/AF2 interaction.

scholarly journals Effects of Progesterone on Nuclear and Cytosol Steroid Receptor Levels in the Oestrogen-stimulated Uterus: Comparison of the Sheep and Mouse

1982 ◽  
Vol 35 (4) ◽  
pp. 403 ◽  
Author(s):  
GM Stone ◽  
C McCaffery ◽  
BG Miller
Keyword(s):  
Binding Site ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Direct Effect ◽  
Dissociation Constants ◽  
Single Injection ◽  
Steroid Receptor ◽  
Scatchard Analysis ◽  
Mouse Uterus ◽  
Receptor Level

Methods for the measurement of nuclear receptors for oestradiol (Ez) and progesterone (P) in mouse uterus and sheep endometrium have been established. Scatchard analysis of nuclear receptors gave the following dissociation constants (nM) and binding site concentrations (pmol steroid/mg DNA): Ez receptor, mouse 3� 76 and 2� 68, sheep 2� 03 and 5� 37; P receptor, mouse 5� 77 and 2� 52, sheep 5 34 and 3� 58. The effects of a single injection of P on nuclear and cytosol levels of Ez and P receptors have been contrasted in these tissues from Ez-treated mice and sheep. In both species, P treatment resulted, in 30-120 min, in depletion of its own cytosol receptor and accumulation of its nuclear receptor. A significant reduction of cytosol E2 receptor was seen only in the mouse at 24 h. P decreased the nuclear Ez-receptor level in the mouse at 2-8 h, but had no such effect in the sheep. The results indicate that the anti-uterotrophic action of P in mouse uterus is caused by an early direct effect of P on nuclear Ez-receptor retention, and appear also to explain why P is not anti-uterotrophic in sheep uterus.

scholarly journals SENP1 Enhances Androgen Receptor-Dependent Transcription through Desumoylation of Histone Deacetylase 1

2004 ◽  
Vol 24 (13) ◽  
pp. 6021-6028 ◽  
Author(s):  
Jinke Cheng ◽  
Dachun Wang ◽  
Zhengxin Wang ◽  
Edward T. H. Yeh
Keyword(s):  
Androgen Receptor ◽  
Histone Deacetylase ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Protein Function ◽  
Potential Role ◽  
Histone Deacetylase 1 ◽  
Repressive Effect ◽  
Specific Protease

ABSTRACT SUMO (also called Sentrin) is a ubiquitin-like protein that plays an important role in regulating protein function and localization. It is known that several nuclear receptors are modified by SUMO; however, the effect of desumoylation in regulating nuclear receptor function has not been elucidated. Here we show that androgen receptor (AR)-mediated transcription is markedly enhanced by SENP1, a member of SUMO-specific protease family. SENP1's ability to enhance AR-dependent transcription is not mediated through desumoylation of AR, but rather through its ability to deconjugate histone deacetylase 1 (HDAC1), thereby reducing its deacetylase activity. HDAC1's repressive effect on AR-dependent transcription could be reversed by SENP1 and by deletion of its sumoylation sites. RNA interference depletion of endogenous HDAC1 also reduced SENP1's effect. Thus, SENP1 could regulate AR-dependent transcription through desumoylation of HDAC1. These studies provide insights on the potential role of desumoylation in the regulation of nuclear receptor activity.

A SOLUBLE ANDROGEN RECEPTOR IN THE CYTOPLASM OF RAT PROSTATE

1969 ◽  
Vol 45 (4) ◽  
pp. 531-541 ◽  
Author(s):  
W. I. P. MAINWARING
Keyword(s):  
Molecular Weight ◽  
Androgen Receptor ◽  
Nuclear Receptor ◽  
Sedimentation Coefficient ◽  
Binding Specificity ◽  
Supernatant Fraction ◽  
Soluble Receptor ◽  
Tryptophan Residues ◽  
Rat Prostate ◽  
Androgen Binding

SUMMARY A thermolabile protein with the properties of a steroid 'receptor' was identified in the cytoplasmic or 105,000 g supernatant fraction of the rat prostate. The receptor has a particular binding specificity towards 5αdihydrotestosterone. Testosterone is bound to a lesser extent but other steroids, including certain androgenic hormones, are not bound. The sedimentation coefficient of 8·0 s and the frictional ratio of 1·96, equivalent to a molecular weight of 2·74 × 105, clearly distinguish the soluble androgen-receptor from the androgen-binding globulin in serum and the androgen-receptor in the prostatic nucleus. Like the nuclear receptor, however, the soluble receptor is probably an acidic protein. Both cysteine and tryptophan residues appear necessary for maintaining the functional configuration of the receptor.

Effect of lisuride and cyproterone acetate on the prostatic androgen receptor of hypophysectomized rats

1986 ◽  
Vol 113 (1_Suppl) ◽  
pp. S154-S155 ◽  
Author(s):  
H. MOELLER ◽  
TH. GOERLICH ◽  
A. HAUG ◽  
B. GOECKE
Keyword(s):  
Androgen Receptor ◽  
Cyproterone Acetate ◽  
Hypophysectomized Rats
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