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At least 19 recordsLinked to original sources
PubMed1978

Comparison between different forms of estrogen cytosol receptor and the nuclear receptor extracted by micrococcal nuclease.

As an approach to the mechanism of the nuclear translocation of estrogen receptor, the estradiol nuclear receptor (RN) of lamb endometrium was extracted with micrococcal nuclease at 2--4 degrees and compared to the "native" 8S and to the Ca2+-transformed cytosol receptors. After extensive digestion of chromatin, giving up to 10% perchloric acid-soluble DNA and a majority of nucleosome monomers, up to 80% of the RN was extracted and under low ionic strength. This RN was found to be completely different from the partially proteolyzed Ca2+-transformed cytosol receptor. It migrated with a sedimentation constant of 4 and 6 S. The Stokes radius of the predominant form as determined by ACA 34 chromatography was 5.3 nm. The calculated apparent molecular weights were 130,000 and 90,000, respectively. The RN was able to bind DNA and was eluted from a diethylaminoethyl cellulose column at 0.23 and 0.30 M KCl. We conclude that the mechanism proposed by Puca et al., according to which the Ca2+-transformed cytosol receptor is split by a Ca2+ receptor-transforming factor into a smaller form able to cross the nuclear membrane, is very unlikely.

Animals↗
PubMed1979

Relationship of receptor affinity to the modulation of thyroid hormone nuclear receptor levels and growth hormone synthesis by L-triiodothyronine and iodothyronine analogues in cultured GH1 cells.

We have previously demonstrated that L-triiodothyronine (L-T3) induces an increase in growth hormone synthesis and messenger RNA in cultured GH1 cells, a rat pituitary cell line. In addition to regulating the growth hormone response, L-T3 elicits a time- and dose-dependent reduction in the level of its nuclear receptor, which is a direct function of the occupancy of the receptor binding site. In this study we have compared the relative affinity of L-T3, triiodothyroacetic acid, D-triiodothyronine (D-T3), and L-thyroxine (L-T4) for the receptor with the induction of the growth hormone synthesis and the ability of these compounds to elicit a reduction in thyroid hormone nuclear receptor levels. Triiodothyroacetic acid and D-T3 were specifically examined because the biologic effect of these compounds in the intact rat is significantly lower than predicted by their affinity for the receptor using isolated rat liver nuclei in vitro. In intact cells each compound demonstrated an excellent relationship between the relative receptor affinity, the induction of growth hormone production, and the concentration-dependent reduction in nuclear receptor levels. With the exception of D-T3, the relative affinity of iodothyronine was identical for the receptor using intact cells in serum-free media, or isolated GH1 cell nuclei in vitro. The apparent receptor affinity of D-T3 with intact cells was 5.5-fold lower than with isolated nuclei, which suggests a decrease in cell entry of D-T3 relative to the other iodothyronines. Quantitation of the [125I]iodothyronine associated with the receptor in GH1 cells after a 36-h incubation with L-125I-T4 was 90% L-T4 and 10% L-T3, which indicates that the major effect of L-T4 in GH1 cells is a result of intrinsic L-T4 activity. Studies with dispersed rat anterior pituitary cells demonstrated that L-T3 induces growth hormone synthesis and elicits a reduction in nuclear receptor levels in the same fashion as GH1 cells. The observation that thyroid hormone influences dispersed rat pituitary cells in a fashion qualitatively similar to GH1 cells may have implications for the growth hormone response of the somatotroph cell in vivo to different thyroidal states.

Animals↗
PubMed2026

Functional perturbation reveals context-dependent contributions of nuclear receptors to drug-induced hepatic steatosis.

Drug-induced hepatic steatosis is mediated by diverse molecular mechanisms, yet several nuclear receptors have been proposed as molecular initiating events or early key events within adverse outcome pathways for hepatic steatosis. However, direct functional evidence supporting these mechanistic roles in human-relevant experimental systems remains limited. The present study evaluated the contribution of selected nuclear receptors to drug-induced hepatic steatosis using complementary human hepatic in vitro models. Stable short hairpin RNA-mediated knockdown of individual nuclear receptors was established in HepG2 and differentiated HepaRG cells, followed by exposure to representative steatogenic drugs, including valproic acid, amiodarone, tamoxifen, and rifampicin. In parallel, primary human hepatocyte spheroids were used to compare drug-induced lipid accumulation with direct pharmacological activation of individual nuclear receptor pathways. While depletion of multiple nuclear receptors markedly affected oleic acid-induced lipid accumulation, drug-induced steatogenic responses exhibited predominantly selective and compound-specific receptor dependencies. In differentiated HepaRG cells, nuclear receptor depletion influenced basal lipid homeostasis more strongly than valproic acid-induced lipid accumulation. Conversely, direct activation of liver X receptor and peroxisome proliferator-activated receptors α and γ in primary human hepatocyte spheroids induced robust lipid accumulation, whereas most steatogenic drugs produced comparatively modest responses. These findings demonstrate that the contribution of individual nuclear receptors to drug-induced hepatic steatosis is highly compound- and context-dependent and cannot be explained by a single conserved receptor pathway. This study provides functional evidence from complementary human-relevant hepatic models that supports refinement of hepatic steatosis adverse outcome pathways and highlights the value of targeted perturbation strategies for mechanistic toxicology.

Adverse outcome pathway, HepaRG↗
PubMed1977

Nuclear receptor estrogen complex in the pineal gland. Modulation by sympathetic nerves.

Pineal nuclear receptor estradiol complex determined by the 3H-estradiol exchange assay exhibited a Kd = 0.42 nM. Its concentration was maximal at proestrus and after administering 2-20 microgram of estradiol to spayed rats. It was also detected in 6-day-old rats, before full maturation of pineal sympathetic nerves is attained. Superior cervical ganglionectomy caused nuclear receptor estrogen complexes (NREC) to decrease by 48 and 65% 5 and 14 days later; estradiol administration brought about increases of complex levels (1.9-2.3-fold) which were significantly smaller than in control or decentralized rats (3.4-3.9-fold). The time course of accumulation and retention of nuclear complexes was not affected by ganglionectomy. Isoproterenol restored the basal levels of NREC, but inhibited the effects of estradiol on complex accumulation; propranolol, administered simultaneously with estradiol also inhibited estrogen effects on the pineal. Estradiol incubation in vitro increased pineal nuclear receptor hormone levels and enhanced the conversion of serotonin into melatonin and 5-methoxytryptophol; no changes in hydroxyindole-O-methyl transferase (HIOMT) activity were detected. These data support the conclusion that accumulation and retention of pineal NREC are under partial dependence upon sympathetic nerves.

Acetylserotonin O-Methyltransferase↗
PubMed1979

Roentgenographic contrast agents inhibit triiodothyronine binding to nuclear receptors in vitro.

The ability of roentgenographic contrast agents to inhibit binding of [125I]T3 to nuclear receptors was studied during incubation of rat liver nuclei or nuclear extracts in vitro and after ip administration of the agents in vivo. Ipodate, iodipamide, iopanoic acid, and diatrizoate inhibited binding of [125I]T3 in vitro. The most potent inhibitor was ipodate, which produced 50% inhibition of binding at 1.2 X 10(-4) M. When given orally in acute in vivo experiments, ipodate did not diminish binding to liver nuclear receptors. Ipodate appeared to inhibit in vivo metabolism of [125I]T3.

Animals↗
PubMed2013

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.

Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

ACTH-Secreting Pituitary Adenoma↗
PubMed2026

Genome-wide chromatin profiling reveals a nonlimiting role for RXR in macrophage-like cells stimulated with multiple nuclear receptor agonists.

Retinoid X receptor (RXR) is an obligate heterodimerization partner for many nuclear receptors. In the absence of ligands, RXR occupies thousands of genomic regions, with its binding landscape predominantly determined by cell identity. In the presence of agonists of RXR or its partners, RXR occupancy is changed at a subset of binding regions. The characteristics of these ligand-responsive binding regions remain largely unexplored. We used ChIP-seq to profile RXR occupancy in PMA-differentiated THP-1 cells treated with agonists of RXR or partner receptors, including RARα, VDR, PPARδ, PPARγ, LXRs, and TR, or a "cocktail" containing multiple agonists. The RXR agonist LG268 produced a stronger increase in RXR occupancy than any of the six partner-receptor agonists or their combination. The relevance of ligand-induced RXR peaks was confirmed by the analyses of motif enrichment and RXR occupancy at regulatory elements of target genes. RXR binding was investigated in more detail in cells treated with the VDR agonist, calcitriol. Calcitriol markedly enhanced VDR binding, but the corresponding increase in RXR occupancy was less pronounced. We found that both ligand-induced and unresponsive RXR peaks were involved in gene regulation, and only a small subset (∼3%) of calcitriol-regulated genes exhibited decreases in both RXR binding and mRNA levels in response to combined agonist treatment. These results support a model in which RXR functions as a nonlimiting module in a macrophage-like cell type, and interference between pathways is minimally attributable to RXR sequestration.

Humans↗
PubMed2026

Genomic identification and functional characterization of the nuclear receptor gene family in relation to sex determination and gonad development in the Pacific oyster (Crassostrea gigas).

Nuclear receptors (NRs) are a large superfamily of transcription factors that control a wide range of physiological processes by modulating the expression of downstream target genes. Numerous studies have confirmed that NR family members play critical and conserved roles in sex determination and gonadal development across metazoans. However, in mollusks, systematic characterization of NRs and their potential functions in gonadal regulation remain largely unexplored. In this study, 46 NR gene family members in the Pacific oyster (Crassostrea gigas) were identified and assigned to eight subfamilies. All NR family members contain at least one of the two core domains (DNA-binding domain, DBD; ligand-binding domain, LBD), and conserved exon-intron structures were observed within the same subgroup, indicating their evolutionary conservation. Furthermore, expression profiling revealed high expression of CgNR2F, CgNR5A1-1, and CgNR0B1 in undifferentiated gonads, suggesting their potential involvement in sex determination. CgNR1A and CgNR2E5 were specifically expressed in female gonads and exhibited female-biased expression patterns, indicating a putative role in ovarian development. Moreover, CgNR3A and CgNR3B showed high expression levels during the undifferentiated stage and early male development stage, implying their possible participation in male gonadal development and gametogenesis. These results expand the understanding of the NR gene family in C. gigas and help elucidate the potential functions of NR genes in sex determination and gonadal development.

Animals↗
PubMed1976

Dose-dependent depletion of nuclear receptors by L-triiodothyronine: evidence for a role in induction of growth hormone synthesis in cultured GH1 cells.

The relationship between the binding of L-triiodothyronine (T3) to nuclear receptors and the induction of growth hormone synthesis was examined in cultured GH1 cells, a rat pituitary cell line. After 24 hr, T3 induced a maximal 4-fold increase in the rate of growth hormone wynthesis; the T3 concentration that induced a half-maximal increase was 0.22 nM. The biologic dose-response curve was shifted to the left of the receptor occupancy curve (Kd = 0.5 nM) by a factor of approximately 2 when receptor binding was examined for 4 hr but showed a significantly closer agreement when examined for the same 24-hr period as the biologic response. This shift in the fractional occupancy curve is not due to further equilibration but occurs as a result of a time- and dose-dependent depletion of the nuclear receptor by T3.

Cell Line↗
PubMed2026

BHLHE40 and ChREBP associate with hepatic enhancer clusters containing PPARα, RXRα, and HNF4 nuclear receptors.

BHLHE40/DEC1 is a basic helix-loop-helix transcription factor (TF) that regulates circadian rhythm and T-cell responses. In hepatocytes, its function and interplay with other TFs are poorly understood. Employing a genome-wide approach, we show that its genomic binding strongly overlapped with that of carbohydrate response-element binding protein, a sugar-sensing TF and known inducer of BHLHE40 expression. Transcriptomic analysis of primary mouse hepatocytes revealed reduced expression of genes involved in genomic stability on Bhlhe40 knockdown by siRNA. Bhlhe40 depletion potentiated fructose responsiveness of genes involved in cell-cycle regulation. Strikingly, genomic binding of BHLHE40 extensively overlapped with enhancers occupied by PPARα, RXRα, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPARα target genes. Using HEK293 cells, we further observed that BHLHE40 physically interacted with RXRα and PPARα cofactors. Collectively, our data suggest that through cooperation with carbohydrate response-element binding protein and nuclear receptors, BHLHE40 is a central regulator of hepatic gene expression with potential to integrate inputs from nutrient signals contributing to the metabolic flexibility of the liver.

Animals↗
PubMed1979

The cyclic relationship of estrogen sulfurylation to the nuclear receptor level in human endometrial curettings.

Human endometrial curettings were selected principally from patients undergoing tubal ligations for elective sterilization. Specimens were analyzed for the metabolism of 17beta-[6,7-3H]estradiol and Na2 35SO4; assayed for the nuclear receptor content with 17beta-[6,7-3H]estradiol; and examined for the cytosol receptor content with 17beta-[2,4,6,7-3H]estradiol. The results of these experiments demonstrated that a) estrogen sulfotransferase activity is greatly stimulated during the secretory phase; b) although estrogen dehydrogenase is active throughout the menstrual cycle, the formation of estrone is elevated in concert with sulfurylation; and c) this increased metabolism of 17beta-estradiol is accompanied by a decreased nuclear uptake of the estrogen receptor complex. The importance of this endometrial estrogen metabolism in the maintenance of a secretory tissue is discussed.

Animals↗
PubMed1977

Concentration of L-thyroxine and L-triiodothyronine specifically bound to nuclear receptors in rat liver and kidney. Quantitative evidence favoring a major role of T3 in thyroid hormone action.

To estimate the relative contribution of l-triiodothyronine (T(3)) and l-thyroxine (T(4)) to thyroidal effects, we have measured the concentration of iodothyronine bound to specific hepatic nuclear receptor sites by three different techniques: (a) specific radioimmunoassay after separation of T(3) and T(4) by preparative paper chromatography; (b) in vivo kinetic approaches as reported previously; and (c) isotopic equilibration. By these three methods, receptor concentration of T(3) and T(4) in liver was 0.51+/-0.19 (SD) and 0.08+/-0.06; 0.52+/-0.12 and 0.08+/-0.02; and 0.50+/-0.13 and 0.10+/-0.03 pmol/mg DNA, respectively. The percentage contribution of T(3) and T(4) to total receptor iodothyronine was thus 86.8+/-9.0 and 13.2+/-9.4; 86.3+/-3.5 and 13.7+/-3.5; and 83.7+/-5.6 and 16.3+/-5.6%, respectively. In kidney, specifically bound nuclear T(3) and T(4) were estimated both by isotopic equilibration and by in vivo kinetic techniques to be 0.28+/-0.11 and 0.03+/-0.01 pmol/mg DNA, respectively. Thus, T(3) constituted 89.4+/-3.2% of total receptor iodothyronine in this tissue. No other iodothyronines or analogs were bound to the nuclear sites in either tissue. Kidney and liver nuclear T(3) concentrations also were identical to values previously reported with in vivo kinetic techniques. Other studies from this laboratory have suggested that thyroid effect is related to the molar concentration of iodothyronine bound to specific nuclear sites, that the sites are similar in various tissues, and that iodothyronine in plasma is in equilibrium with nuclear T(3). If these relationships are assumed, T(3) contributes between 85 and 90% of thyroidal effects in the euthyroid rat. The remaining 10-15% of thyroidal effect appears to result from the intrinsic activity of T(4).

Animals↗
PubMed2025

Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells Using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2.

UNLABELLED: FOXA1 is a pioneer transcription factor essential for chromatin accessibility and transcriptional regulation in hormone-driven cancers. In breast cancer, FOXA1 plays a central role in facilitating nuclear receptor binding, reprogramming enhancer landscapes, and promoting transcriptional changes associated with therapy resistance. Whereas FOXA1's function has been primarily studied in the context of estrogen receptor-α (ER), its broader protein interaction network remains incompletely defined. In this study, we systematically map FOXA1-interacting proteins in ER-positive breast cancer cells using proximity-dependent biotin labeling (miniTurbo) combined with quantitative LC-MS/MS proteomics. We engineered MCF-7 cell lines stably expressing miniTurbo-tagged FOXA1 at either the N-terminus or C-terminus to ensure comprehensive coverage of interaction interfaces. This approach recovered known FOXA1 partners, including AR, MLL3, YAP1, and GATA3, and identified 157 previously unreported FOXA1 interactors. Notably, 42 of these novel partners, including NR2C2, were significantly associated with poor relapse-free survival in patients with ER-positive breast cancer. To demonstrate the utility of this resource, we characterized the FOXA1-NR2C2 interaction in depth. Integrating chromatin immunoprecipitation sequencing and RNA sequencing, we show that FOXA1 and NR2C2 co-occupy a subset of genomic regions and drive co-regulated transcriptional programs involved in tumor progression. Our study reveals an expanded FOXA1 interactome and new insights into its functional network in breast cancer, providing candidate proteins for further exploration as biomarkers or therapeutic targets. IMPLICATIONS: These findings expand the FOXA1 interactome in breast cancer and uncover new candidate proteins with potential as biomarkers and therapeutic targets in hormone-driven tumors.

Humans↗
PubMed1978

Uncharged nuclear receptors for estrogen in breast cancers.

This study was undertaken to define the incidence and concentration of uncharged nuclear estrogen receptors (RN) in human breast cancer. The concentrations of RN and cytoplasmic uncharged receptor were determined on sucrose gradients following a 4-hr incubation at 4 degrees with 1.6 nM 17 beta-[3H]estradiol in 139 tumor specimens from 137 patients. RN was extracted from washed nuclear pellets in buffer containing 0.4 M KCl. The receptor molecule extracted had a high affinity for 17 beta-[3H]estradiol (Kd = 0.9 to 7.6 nM) and was specific for estrogen. The possibility of artifact due cytoplasmic contamination of the nuclear fraction or high-ionic-strength-induced exchange of charged nuclear receptors was rendered unlikely by validation experiments performed with pooled tumor tissue. Significant amounts of cytoplasmic uncharged receptor (greater than 7 fmol/mg protein) were found in 63.3% of the tumors. Similar significant amounts of RN were found in 29.5% of the tumors. Significant amounts of RN in the presence of undetectable cytoplasmic uncharged receptor were found in 2.9% of the tumors. The percentage of tumors that contain significant amounts of RN is approximately the same percentage of estrogen receptor-positive tumors that do not respond to ablative therapy.

Adult↗
PubMed1975

Effects of estrogen on gene expression in chick oviduct: nuclear receptor levels and initiation of transcription.

Estrogen (diethylstilbesterol) was administered in vivo to chicks for various time periods. Chromatin was then prepared from oviduct nuclei and assayed for its capacity to support initiation of RNA chain synthesis in vitro in the presence of saturating levels of Escherichia coli RNA polymerase (RNA nucleotidyltransferase; nucleosidetriphosphate:RNA nucleotidyltransferase; EC 2.7.7.6). These same nuclei were also assayed by a [3H]estradiol exchange assay for their endogenous receptor content. The number of available initiation sites for RNA synthesis on chromatin was shown to correlate with the endogenous levels of nuclear estrogen receptor. A decrease in the nuclear concentration of estrogen receptor molecules and the concentration of initiation sites for RNA synthesis occurred during withdrawal of estrogen from previously stimulated chicks. Both parameters declined with a similar half-life. When estrogen was readministered to withdrawn chicks, the number of initiation sites increased 2-fold as early as 30 min and approached a maximal level (3-fold) by 1 hr. During the same period of restimulation with estrogen, the number of estrogen receptor molecules bound to nuclei increased to a maximum at 20 min and then declined at 1 hr to a steady-state level 2-fold higher than the withdrawn chicks. Simultaneous measurements of RNA chain length and RNA chain propagation rate demonstrated that parameters remained relatively constant throughout estrogen withdrawal as well as secondary stimulation. The temporal correlation between changes in the levels of nuclear-bound estrogen receptor and the number of RNA chain initiation sites on chromatin prepared from these same nuclei strongly suggested that the hormone receptor complexes act on chromatin to mediate these changes in genetic transcriptional activity.

Animals↗
PubMed1977

Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor?

High resolution X-ray analysis of the hormone-binding protein prealbumin has shown that it has a structural complementarity to double-helical DNA. The proposed binding site is composed of two symmetry-related beta-sheets containing a pair of helically disposed arms, which can interact with the bases in the wide groove of DNA. A palindromic target sequence is indicated by the symmetry of the protein. The two identical thyroid hormone binding sites on prealbumin are located in a channel that runs completely through the molecule. These two structural features suggest prealbumin as a model for the thyroid hormone nuclear receptor, providing a number of detailed predictions of its properties.

Amino Acid Sequence↗