Association of glucocorticoid receptors with prostate nuclear sites for androgen receptors and with androgen response elements

1990 ◽  
Vol 5 (2) ◽  
pp. 117-127 ◽  
Author(s):  
P. Davies ◽  
N. K. Rushmere
Keyword(s):  
Glucocorticoid Receptors ◽  
Androgen Receptors ◽  
Steroid Receptors ◽  
Normal Population ◽  
Ventral Prostate ◽  
Response Elements ◽  
High Affinity ◽  
Glucocorticoid Response ◽  
Nuclear Structures

ABSTRACT Ventral prostate glands of intact normal rats contained low levels (2500 molecules/cell) of high-affinity (dissociation constant (Kd) 0·57 nmol/l) glucocorticoid receptors (GR). Levels of GR increased 2·8-fold 1 day after castration, and 4·3-fold 3 days after castration. Nuclear GR increased from a normal value of 1150 molecules/nucleus to 5200 molecules/nucleus 3 days after castration. The greater increase in intranuclear GR was in that associated with oligomeric chromatin. Although nuclear GR never approached the normal population of nuclear androgen receptors (AR; approximately 16000 molecules/nucleus), the selective rise in chromatin-associated receptors ensured that almost 60% of chromatin sites remained occupied. GR associated with prostate nuclear structures in a similar manner to AR, and exogenous GR bound saturably and with high affinity (Kd 100 pmol/1) to a similar number of sites as did AR. Both steroid receptors apparently competed for the same sites. In DNA—cellulose competition analyses, synthetic oligonucleotides containing glucocorticoid response elements or putative androgen response elements competed similarly against immobilized non-specific DNA for both AR and GR. In view of these data and information from other sources, it is probable that the role of GR in the prostate should be assessed with a view to understanding its action under conditions of androgen deprivation.

Molecular cloning of human and rat complementary DNA encoding androgen receptors

Science ◽  
1988 ◽  
Vol 240 (4850) ◽  
pp. 324-326 ◽  
Author(s):  
CS Chang ◽  
J Kokontis ◽  
ST Liao
Keyword(s):  
Androgen Receptors ◽  
Steroid Receptors ◽  
Ventral Prostate ◽  
Cdna Libraries ◽  
Human Testis ◽  
Dna Binding Domain ◽  
Dna Encoding ◽  
High Affinity ◽  
Autoimmune Antibodies ◽  
Rat Ventral Prostate

Complementary DNAs (cDNAs) encoding androgen receptors were obtained from human testis and rat ventral prostate cDNA libraries. The amino acid sequence deduced from the nucleotide sequences of the cDNAs indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors. The human cDNA was transcribed and the RNA product was translated in cell-free systems to yield a 76-kilodalton protein. The protein was immunoprecipitable by human autoimmune antibodies to the androgen receptor. The protein bound androgens specifically and with high affinity.

scholarly journals The permissive role of glucocorticoids on interleukin-1 stimulation of angiotensinogen gene transcription is mediated by an interaction between inducible enhancers.

1990 ◽  
Vol 10 (8) ◽  
pp. 4389-4395 ◽  
Author(s):  
D Ron ◽  
A R Brasier ◽  
K A Wright ◽  
J F Habener
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Interleukin 1 ◽  
Luciferase Reporter ◽  
Nf Kappa B ◽  
Response Elements ◽  
Glucocorticoid Response ◽  
Glucocorticoid Response Elements ◽  
Permissive Role

The acute-phase activation of the rat angiotensinogen (rAT) gene in liver cells is a transcriptional event mediated through an interleukin-1-inducible, NF kappa B-binding, cis-acting element (the acute-phase response element [APRE]). Using a cell culture model for the acute-phase response, we showed that the increase in angiotensionogen mRNA in H35 rat hepatoma cells requires costimulation with glucocorticoids and cytokines. Stably transfected rAT promoter-luciferase reporter genes were also activated by cytokines only in the presence of glucocorticoids. This permissive role of glucocorticoids is dependent on the expression of functional glucocorticoid receptors, because in HepG2 cells naturally deficient in such receptors, rAT gene-luciferase reporter constructs responded to interleukin-1 only when cotransfected with an expression vector for the glucocorticoid receptor. Point mutations in the two rAT gene glucocorticoid response elements located adjacent to the APRE led to loss of interleukin-1 inducibility. Induction of luciferase activity in transfected cells occurred even in the presence of cycloheximide, demonstrating that this synergistic response did not depend on new protein synthesis. Thus, a direct interaction between the interleukin-1-inducible NF kappa B-binding APRE and glucocorticoid response elements, located in cis, underlies the acute-phase activation of the rAT gene.

ANDROGEN RECEPTORS IN PROLACTIN PRODUCING PITUITARY TUMOURS IN RATS

1977 ◽  
Vol 86 (2) ◽  
pp. 288-298 ◽  
Author(s):  
Arne Attramadal ◽  
Oddvar Naess ◽  
Egil Haug ◽  
Vidar Hansson ◽  
Ken Purvis
Keyword(s):  
Androgen Receptor ◽  
Binding Sites ◽  
Androgen Receptors ◽  
Sedimentation Coefficient ◽  
Ventral Prostate ◽  
Scatchard Analysis ◽  
Receptor Complex ◽  
Pituitary Tumours ◽  
High Affinity ◽  
Androgen Binding

ABSTRACT The androgen receptor system in prolactin secreting oestrogen induced pituitary tumours has been studied. The tumour cytosol was found to contain specific androgen receptors binding [3H]5α-dihydrotestosterone (DHT) and [3H] testosterone (T) with high affinity and low capacity. Scatchard analysis of the saturation data for T revealed one class of high affinity binding sites. The equilibrium constant of dissociation (Kd) was ∼ 4 × 10−10 m and the number of binding sites was calculated to be 12.8 femtomoles/mg protein. The sedimentation coefficient of the androgen receptor complex in low salt sucrose gradients was ∼ 7 S, the electrophoretic mobility (RF) in 3.25 % polyacrylamide gels ∼ 0.5 and the isoelectric point 5.8. The protein nature of the receptor was indicated by the finding that protease, but not DNase and RNase, eliminated androgen binding. Furthermore, the receptor was thermolabile and functionally dependent on free SH-groups since androgen binding was eliminated by heating 45°C for 30 min) and treatment with p-chloromercuriphenyl sulphonate (1 mm). Steroid specificity was tested in vitro by examining the competing efficiency of different unlabelled steroids for the binding of [3H]T. The affinity of DHT for the receptor was approximately twice that of testosterone while the binding affinity of oestradiol-17β and progesterone was very low. Cortisol had no affinity for the androgen receptor. The dissociation of the androgen receptor complex was very slow at 0°C (t ½ > 48 h). Thus, the characteristics of the cytoplasmic androgen receptors of the prolactin producing pituitary tumours are very similar to those of the androgen receptors earlier demonstrated in the anterior pituitary, hypothalamus, ventral prostate, epididymis and testis. The presence of specific androgen receptors in prolactin producing pituitary tumours indicates that androgen is involved in the regulation of synthesis and release of prolactin.

scholarly journals Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products

2004 ◽  
Vol 181 (2) ◽  
pp. 207-221 ◽  
Author(s):  
JI Webster ◽  
EM Sternberg
Keyword(s):  
Mortality Rate ◽  
Hpa Axis ◽  
Glucocorticoid Receptors ◽  
Viral Infections ◽  
Lethal Effects ◽  
Hypothalamic Pituitary Adrenal ◽  
Glucocorticoid Response ◽  
Pituitary Adrenal Axis ◽  
Synthetic Glucocorticoid

The hypothalamic-pituitary-adrenal (HPA) axis is activated during many bacterial and viral infections, resulting in an increase in circulating glucocorticoid levels. This HPA axis activation and glucocorticoid response are critical for the survival of the host, as demonstrated by the fact that removal of the HPA axis (by adrenalectomy or hypophysectomy) or glucocorticoid receptor (GR) blockade enhances the severity of the infection and in some cases enhances the mortality rate. Replacement with a synthetic glucocorticoid reverses these effects by reducing the severity of the infection and provides protection against lethal effects. In addition, some bacteria and viral infections have been shown to affect the GR directly. These have been described and the implications of such an effect discussed.

Disorders of the adrenal cortex

2020 ◽  
pp. 2331-2360
Author(s):  
Mark Sherlock ◽  
Mark Gurnell
Keyword(s):  
Adrenal Cortex ◽  
Gene Transcription ◽  
Sex Steroids ◽  
Glucocorticoid Receptors ◽  
Steroid Hormone ◽  
Response Elements ◽  
Glucocorticoid Response ◽  
Clinical Consequences ◽  
Glucocorticoid Response Elements ◽  
Target Gene Transcription

Three classes of steroid hormone are produced by the adrenal cortex after uptake of precursor cholesterol from the plasma—mineralocorticoids, glucocorticoids, and sex steroids—with classical endocrine feedback loops controlling their secretion. Glucocorticoids have more diverse and extensive roles than mineralocorticoids, regulating sodium and water homeostasis, glucose and carbohydrate metabolism, inflammation, and stress. These effects are mediated by the interaction of cortisol with ubiquitous glucocorticoid receptors, and the induction or repression of target gene transcription (via glucocorticoid response elements, GREs). Adrenocortical diseases are relatively uncommon, but they have detrimental clinical consequences and can be treated effectively. Hormonal deficiency or excess is usually the result of abnormal secretion.

scholarly journals Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains

1999 ◽  
Vol 341 (3) ◽  
pp. 515-521 ◽  
Author(s):  
Erik SCHOENMAKERS ◽  
Philippe ALEN ◽  
Guy VERRIJDT ◽  
Ben PEETERS ◽  
Guido VERHOEVEN ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Glucocorticoid Receptors ◽  
Response Element ◽  
Response Elements ◽  
Dna Binding Domains ◽  
High Affinity ◽  
Binding Domains

The androgen and glucocorticoid hormones evoke specific in vivo responses by activating different sets of responsive genes. Although the consensus sequences of the glucocorticoid and androgen response elements are very similar, this in vivo specificity can in some cases be explained by differences in DNA recognition between both receptors. This has clearly been demonstrated for the androgen response element PB-ARE-2 described in the promoter of the rat probasin gene. Swapping of different fragments between the androgen- and glucocorticoid-receptor DNA-binding domains demonstrates that (i) the first Zn-finger module is not involved in this sequence selectivity and (ii) that residues in the second Zn-finger as well as a C-terminal extension of the DNA-binding domain from the androgen receptor are required. For specific and high-affinity binding to response elements, the DNA-binding domains of the androgen and glucocorticoid receptors need a different C-terminal extension. The glucocorticoid receptor requires 12 C-terminal amino acids for high affinity DNA binding, while the androgen receptor only involves four residues. However, for specific recognition of the PB-ARE-2, the androgen receptor also requires 12 C-terminal residues. Our data demonstrate that the mechanism by which the androgen receptor binds selectively to the PB-ARE-2 is different from that used by the glucocorticoid receptor to bind a consensus response element. We would like to suggest that the androgen receptor recognizes response elements as a direct repeat rather than the classical inverted repeat.

The permissive role of glucocorticoids on interleukin-1 stimulation of angiotensinogen gene transcription is mediated by an interaction between inducible enhancers

1990 ◽  
Vol 10 (8) ◽  
pp. 4389-4395
Author(s):  
D Ron ◽  
A R Brasier ◽  
K A Wright ◽  
J F Habener
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Interleukin 1 ◽  
Luciferase Reporter ◽  
Nf Kappa B ◽  
Response Elements ◽  
Glucocorticoid Response ◽  
Glucocorticoid Response Elements ◽  
Permissive Role

The acute-phase activation of the rat angiotensinogen (rAT) gene in liver cells is a transcriptional event mediated through an interleukin-1-inducible, NF kappa B-binding, cis-acting element (the acute-phase response element [APRE]). Using a cell culture model for the acute-phase response, we showed that the increase in angiotensionogen mRNA in H35 rat hepatoma cells requires costimulation with glucocorticoids and cytokines. Stably transfected rAT promoter-luciferase reporter genes were also activated by cytokines only in the presence of glucocorticoids. This permissive role of glucocorticoids is dependent on the expression of functional glucocorticoid receptors, because in HepG2 cells naturally deficient in such receptors, rAT gene-luciferase reporter constructs responded to interleukin-1 only when cotransfected with an expression vector for the glucocorticoid receptor. Point mutations in the two rAT gene glucocorticoid response elements located adjacent to the APRE led to loss of interleukin-1 inducibility. Induction of luciferase activity in transfected cells occurred even in the presence of cycloheximide, demonstrating that this synergistic response did not depend on new protein synthesis. Thus, a direct interaction between the interleukin-1-inducible NF kappa B-binding APRE and glucocorticoid response elements, located in cis, underlies the acute-phase activation of the rAT gene.

Role of molecular chaperones in steroid receptor action

2004 ◽  
Vol 40 ◽  
pp. 41-58 ◽  
Author(s):  
William B Pratt ◽  
Mario D Galigniana ◽  
Yoshihiro Morishima ◽  
Patrick J M Murphy
Keyword(s):  
Transcriptional Activation ◽  
Protein Trafficking ◽  
Steroid Receptors ◽  
Transcriptional Regulatory ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Receptor Action ◽  
Binding Cleft ◽  
Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

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