scholarly journals Unoccupied nuclear oestrogen receptors in the female rat hypothalamus. Increases on oestrogen administration

1980 ◽  
Vol 190 (3) ◽  
pp. 833-837 ◽  
Author(s):  
J O White ◽  
L Lim
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Female Rat ◽  
Oestrogen Receptors ◽  
Rat Hypothalamus ◽  
Active Elements

A major proportion of the hypothalamic nuclear oestrogen receptors were available for complexing with radioactive oestradiol in vitro at 4 degrees C and were apparently unoccupied . At 6 h after oestradiol administration the content of unoccupied nuclear receptors had increased 2.5-fold and represented 71% of the total nuclear receptor content. These results suggest that unoccupied receptors may be active elements in the ‘long-term’ receptor population of the hypothalamus. Androgenized females had lower contents of these receptors.

scholarly journals Developmental changes in the content of oestrogen receptors in the hypothalamus of the female rat

1979 ◽  
Vol 184 (2) ◽  
pp. 465-468 ◽  
Author(s):  
J O White ◽  
C Hall ◽  
L Lim
Keyword(s):  
Nuclear Receptors ◽  
Early Development ◽  
Nuclear Receptor ◽  
Sexual Differentiation ◽  
Fold Increase ◽  
Developmental Changes ◽  
Female Rat ◽  
Oestrogen Receptors

Hypothalamic cytosol and nuclear oestrogen receptors are present at birth. A 2-fold increase in cytoplasmic receptor content occurs by the second week, whereas the first significant and equivalent increase in nuclear receptor occurs in the fourth week. The latter reflects reported increases in oestradiol availability thought to lead to complete feminine sexual differentiation. The presence of nuclear receptors in the newborn suggests a requirement for oestrogenic stimulation in early development.

scholarly journals The DRIP Complex and SRC-1/p160 Coactivators Share Similar Nuclear Receptor Binding Determinants but Constitute Functionally Distinct Complexes

2000 ◽  
Vol 20 (8) ◽  
pp. 2718-2726 ◽  
Author(s):  
Christophe Rachez ◽  
Matthew Gamble ◽  
Chao-Pei Betty Chang ◽  
G. Brandon Atkins ◽  
Mitchell A. Lazar ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Transcriptional Activation ◽  
Thyroid Hormone Receptor ◽  
Nuclear Receptor Coactivators ◽  
Nuclear Extracts ◽  
Sequence Requirements

ABSTRACT Transcriptional activation requires both access to DNA assembled as chromatin and functional contact with components of the basal transcription machinery. Using the hormone-bound vitamin D3receptor (VDR) ligand binding domain (LBD) as an affinity matrix, we previously identified a novel multisubunit coactivator complex, DRIP (VDR-interacting proteins), required for transcriptional activation by nuclear receptors and several other transcription factors. In this report, we characterize the nuclear receptor binding features of DRIP205, a key subunit of the DRIP complex, that interacts directly with VDR and thyroid hormone receptor in response to ligand and anchors the other DRIP subunits to the nuclear receptor LBD. In common with other nuclear receptor coactivators, DRIP205 interaction occurs through one of two LXXLL motifs and requires the receptor's AF-2 subdomain. Although the second motif of DRIP205 is required only for VDR binding in vitro, both motifs are used in the context of an retinoid X receptor-VDR heterodimer on DNA and in transactivation in vivo. We demonstrate that both endogenous p160 coactivators and DRIP complexes bind to the VDR LBD from nuclear extracts through similar sequence requirements, but they do so as distinct complexes. Moreover, in contrast to the p160 family of coactivators, the DRIP complex is devoid of any histone acetyltransferase activity. The results demonstrate that different coactivator complexes with distinct functions bind to the same transactivation region of nuclear receptors, suggesting that they are both required for transcription activation by nuclear receptors.

ALTERATIONS INDUCED BY CLOMIPHENE IN THE CONCENTRATIONS OF OESTROGEN RECEPTORS IN THE UTERUS, PITUITARY GLAND AND HYPOTHALAMUS OF FEMALE RATS

1980 ◽  
Vol 87 (3) ◽  
pp. 383-392 ◽  
Author(s):  
E. Y. ADASHI ◽  
A. J. W. HSUEH ◽  
S. S. C. YEN
Keyword(s):  
Pituitary Gland ◽  
Nuclear Receptors ◽  
Single Injection ◽  
Clomiphene Citrate ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Oestrogen Receptors ◽  
Prolonged Retention

Alterations in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus during the 2 weeks following a single administration of clomiphene citrate (Clomid) to immature, bilaterally ovariectomized rats were investigated. Examination of the uterine wet weight at 1, 7 and 14 days following a single injection of Clomid (100 μg, 250 μg or 10 mg) indicated significant time- and dose-related increments from a control value of 45 ± 2 (s.e.m.) mg to a maximum of 123 ± 3 mg (250 μg dose at 14 days). In contrast, a single injection of oestradiol led to a transient increase in the uterine weight on day 1 to 94 ± 6 mg, but was without effect by days 7 and 14. Analysis of the uterine DNA content 7 and 14 days after treatment with Clomid revealed significant increments from control values of 390 ± 10 μg to a high level of 558 ± 8 μg (10 mg dose at 7 days). There was a transient retention of nuclear oestrogen receptors and rapid replenishment of cytoplasmic oestrogen receptors in less than 24 h in the uteri of animals treated with oestradiol (25 μg), but determinations of receptor content in Clomid-treated animals revealed prolonged retention of nuclear receptors and delayed replenishment of cytoplasmic receptors. The duration and extent of retention of nuclear receptors and depletion of cytoplasmic receptors after treatment with Clomid were found to be dose-dependent. Fourteen days after Clomid treatment, levels of oestrogen receptors in nuclei from the uterus were still raised in all treatment groups, whereas replenishment of cytoplasmic receptors was complete in animals treated with the lower doses (100 and 250 μg) of Clomid. A single injection of Clomid (250 μg) induced similar prolonged retention of nuclear receptors and delayed depletion of cytoplasmic receptors in pituitary tissue. In contrast, changes in the content of oestrogen receptors in the hypothalamus following Clomid treatment were minimal. The limited effect of Clomid on hypothalamic tissue may mean that the pituitary gland is a more important target for this compound than is the hypothalamus. The findings have confirmed earlier reports on the long-term uterotrophic effect of Clomid and have suggested that under these long-term, in-vivo conditions, Clomid acts in the uterus and pituitary gland as a long-acting oestrogen characterized by prolonged retention of oestrogen receptors in the nucleus and delayed, but otherwise effective, replenishment of the oestrogen receptors in the cytoplasm.

A possible role of clomiphene citrate in the control of pre-ovulatory LH surge during induction of ovulation

1985 ◽  
Vol 109 (1) ◽  
pp. 58-63 ◽  
Author(s):  
Naoki Terakawa ◽  
Ikuya Shimizu ◽  
Hirohisa Tsutsumi ◽  
Toshihiro Aono ◽  
Keishi Matsumoto
Keyword(s):  
Nuclear Receptor ◽  
Clomiphene Citrate ◽  
Ovariectomized Rats ◽  
Receptor Complex ◽  
Oestrogen Receptors ◽  
Lh Surge ◽  
Serum Lh ◽  
Lh Release

Abstract. A possible role of clomiphene citrate (clomiphene) in the control of ovulation in anovulatory women was investigated. Since a single ip administration of 5 μg oestradiol-17β (E2) to long-term ovariectomized rats did not induce LH surge, the following studies were designed to determine whether pretreatment with clomiphene followed by administration of E2 could induce LH surge in the ovariectomized rats. Changes in cytoplasmic and nuclear oestrogen receptors (ER) were also examined in the pituitaries of these animals. An ip injection of 200 μg clomiphene suppressed serum LH levels significantly for 72 h. The clomiphene injection rapidly caused an elevation of nuclear ER with a concomitant depletion of cytoplasmic ER level in the pituitary and the ER levels remained almost unchaged for 72 h. An administration of E2 12 or 24 h after the clomiphene injection had no significant effects on either the serum LH levels or the cytoplasmic and nuclear ER levels, compared with those induced by clomiphene alone. However, LH surge and the depletion of nuclear ER in the pituitary occurred 24 h later when E2 was injected 48 h after the clomiphene administration. The E2-induced LH release seems to be induced by a replacement of clomiphene by E2 on the nuclear receptor complex. These results suggest that clomiphene may exert actions directly on the pituitary gland to augment oestrogeninduced LH release.

scholarly journals Identification and Characterization of a Tissue-Specific Coactivator, GT198, That Interacts with the DNA-Binding Domains of Nuclear Receptors

2002 ◽  
Vol 22 (1) ◽  
pp. 357-369 ◽  
Author(s):  
Lan Ko ◽  
Guemalli R. Cardona ◽  
Alexandra Henrion-Caude ◽  
William W. Chin
Keyword(s):  
Protein Kinase ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Pituitary Cells ◽  
Tissue Specific ◽  
Dna Binding Domains ◽  
Binding Domains

ABSTRACT Gene activation mediated by nuclear receptors is regulated in a tissue-specific manner and requires interactions between nuclear receptors and their cofactors. Here, we identified and characterized a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. GT198 was originally described as a genomic transcript that mapped to the human breast cancer susceptibility locus 17q12-q21 with unknown function. We show that GT198 exhibits a tissue-specific expression pattern in which its mRNA is elevated in testis, spleen, thymus, pituitary cells, and several cancer cell lines. GT198 is a 217-amino-acid nuclear protein that contains a leucine zipper required for its dimerization. In vitro binding and yeast two-hybrid assays indicated that GT198 interacted with nuclear receptors through their DNA-binding domains. GT198 potently stimulated transcription mediated by estrogen receptor α and β, thyroid hormone receptor β1, androgen receptor, glucocorticoid receptor, and progesterone receptor. However, the action of GT198 was distinguishable from that of the ligand-binding domain-interacting nuclear receptor coactivators, such as TRBP, CBP, and SRC-1, with respect to basal activation and hormone sensitivity. Furthermore, protein kinase A, protein kinase C, and mitogen-activated protein kinase can phosphorylate GT198 in vitro, and cotransfection of these kinases regulated the transcriptional activity of GT198. These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors.

scholarly journals The neurobiology of BRD1 implicates sex-biased dysregulation of nuclear receptor signaling in mental disorders

2018 ◽  
Author(s):  
Anto P. Rajkumar ◽  
Per Qvist ◽  
Sanne H. Larsen ◽  
Ross Lazarus ◽  
Jonatan Pallesen ◽  
...  
Keyword(s):  
Psychiatric Disorder ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Glucocorticoid Receptors ◽  
Target Genes ◽  
Global Gene Expression ◽  
Adult Brain ◽  
Gene Sets ◽  
Disorder Risk

AbstractThe schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/− mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/− mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/− mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/− mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.

scholarly journals The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1192 ◽  
Author(s):  
Philip Marx-Stoelting ◽  
Constanze Knebel ◽  
Albert Braeuning
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Liver Tumors ◽  
Current Knowledge ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Azole Fungicides

Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.

scholarly journals Use of Differential Scanning Fluorimetry as a High-Throughput Assay to Identify Nuclear Receptor Ligands

2012 ◽  
Vol 10 (1) ◽  
pp. nrs.10002 ◽  
Author(s):  
Kara DeSantis ◽  
Aaron Reed ◽  
Raneen Rahhal ◽  
Jeff Reinking
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
High Throughput ◽  
Initial Step ◽  
Estrogen Receptor Α ◽  
Chemical Library ◽  
Differential Scanning Fluorimetry ◽  
Nuclear Receptor Ligands

Identification of ligands that interact with nuclear receptors is both a major biological problem and an important initial step in drug discovery. Several in vitro and in vivo techniques are commonly used to screen ligand candidates against nuclear receptors; however, none of the current assays allow screening without modification of either the protein and/or the ligand in a high-throughput fashion. Differential scanning fluorimetry (DSF) allows unmodified potential ligands to be screened as 10μL reactions in 96-well format against partially purified protein, revealing specific interactors. As a proof of principle, we used a commercially-available nuclear receptor ligand candidate chemical library to identify interactors of the human estrogen receptor α ligand binding domain (ERα LBD). Compounds that interact specifically with ERα LBD stabilize the protein and result in an elevation of the thermal denaturation point, as monitored by the environmentally-sensitive dye SYPRO orange. We successfully identified all three compounds in the library that have previously been identified to interact with ERα, with no false positive results.

Estradiol Modulates Long-Term Synaptic Depression in Female Rat Hippocampus

2000 ◽  
Vol 84 (4) ◽  
pp. 1800-1808 ◽  
Author(s):  
M. Reza Zamani ◽  
Nancy L Desmond ◽  
William B Levy
Keyword(s):  
Functional Organization ◽  
Hippocampal Slices ◽  
Synaptic Depression ◽  
Receptor Activation ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Ovx Rats ◽  
Estradiol Levels

Fluctuating estradiol levels in the adult, female rat modify the anatomical and functional organization of the hippocampal CA1 region. When systemic levels of estradiol are low, e.g., on estrus or in ovariectomized (OVX) rats, long-term synaptic potentiation is difficult to induce in vivo. However, little is known about the role of this ovarian hormone in long-term synaptic depression. Using multiple conditioning paradigms, we assess the magnitude of long-term depression (LTD) at CA3-CA1 synapses in vitro from adult, ovariectomized rats as a function of systemic estradiol replacement. In hippocampal slices from control OVX rats with low levels of estradiol, a low-frequency (2 Hz), asynchronous conditioning stimulation protocol does not produce LTD at 1 h postconditioning. However, this same protocol induces robust LTD in slices from estradiol-treated OVX rats. When the conditioning frequency is increased to 4 Hz, slices from both groups of rats show robust LTD in vitro. At an even higher conditioning frequency (10 Hz), the 2-Hz-based observations are reversed; no consistent changes in synaptic transmission are observed in slices from estradiol-treated OVX rats, but those from control rats (OVX + oil) show robust LTD. Thus estradiol reduces the frequency threshold for LTD induction at the CA3-CA1 synapses. Further, regardless of the conditioning frequency employed, where robust LTD is seen, its induction depends on normally functioning N-methyl-d-aspartate (NMDA) receptors during conditioning. The shift in conditioning frequency needed to elicit LTD is consistent with a decrease in NMDA receptor activation with decreasing estradiol levels.

Sign in / Sign up

Export Citation Format

Share Document