Connecting ligand-induced retinoid X receptor structural dynamics to rexinoid agonist potency
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE199381 | GEO | 2023/01/11
REPOSITORIES: GEO
Similar Datasets
Project description:Rexinoids are agonists of nuclear rexinoid X receptors (RXR) that heterodimerize with other nuclear receptors to regulate gene transcription. A number of selective RXR agonists have been developed for clinical use but their application has been hampered by the unwanted side effects associated with the use of rexinoids and a limited understanding of their mechanisms of action across different cell types. Previous studies from this laboratory showed that treatment of organotypic human epidermis with the low toxicity UAB30 and UAB110 rexinoids resulted in increased steady-state levels of all-trans-retinoic acid (ATRA), the obligatory ligand of the RXR-RAR heterodimers. Here, we investigated the molecular mechanism underlying the increase in ATRA levels using a dominant negative RXRα that lacks the activation function 2 (AF-2) domain. The results demonstrated that overexpression of dnRXRα in human organotypic epidermis markedly reduced signaling by resident ATRA, suggesting the existence of endogenous RXR ligand, diminished the biological effects of UAB30 and UAB110 on epidermis morphology and gene expression, and nearly abolished the rexinoid-induced increase in ATRA levels. Global transcriptome analysis of dnRXRα-rafts in comparison to empty vector-transduced rafts showed that over 95% of the differentially expressed genes in rexinoid-treated rafts constitute direct or indirect ATRA-regulated genes. Thus, the biological effects of UAB30 and UAB110 are mediated through the AF-2 domain of RXRα with minimal side effects in human epidermis. As ATRA levels are known to be reduced in certain epithelial pathologies, treatment with UAB30 and UAB110 may represent a promising therapy for normalizing the endogenous ATRA concentration and signaling in epithelial tissues.
2024-04-02 | GSE244387 | GEO
Project description:Many different molecular mechanisms have been suggested to be associated with PML-RAR dependent transformation of haematopoietic progenitors. Here, we investigated the role of PML-RAR and RXR in the organization of epigenetic structures at a genome-wide level. We identified 2722 high confidence PML-RAR binding sites in the leukemic model cell line NB4 and found PML-RAR colocalization with RXR to the vast majority of these binding regions. Importantly, these results could be corroborated and extended in primary blast cells of two APL patients. Through genome-wide epigenetic studies we show that treatment with pharmacological doses of all-trans retinoic acid ATRA induces global alterations in active H3 acetylation and repressive H3K27me3, H3K9me3 and DNA methylation chromatin modifications. However at the PML-RAR/RXR binding sites, ATRA only induces changes in H3 acetylation. These H3 acetylation alterations triggered by the loss of PML-RAR/RXR binding affect H3 acetylation and RNA polymerase II occupancy at nearby genes. Our results suggest that PML-RAR/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for haematopoietic differentiation, RAR signaling and epigenetic control is crucial to the transforming potential of PML-RAR/RXR. Examination of PML, RARa and RXR binding sites in leukemic cells before and after ATRA treatment, association with transcription via RNAPII occupancy and with chromatin modifications.
2009-12-17 | E-GEOD-18886 | biostudies-arrayexpress
Project description:Haffez2017 - RAR interaction with synthetic
analogues
This model is described in the article:
The molecular basis of the
interactions between synthetic retinoic acid analogues and the
retinoic acid receptors
Hesham Haffez, David R. Chisholm,
Roy Valentine, Ehmke Pohl, Christopher Redfern and Andrew
Whiting
MedChemComm
Abstract:
All-trans-retinoic acid (ATRA) and its synthetic analogues
EC23 and EC19 direct cellular differentiation by interacting as
ligands for the retinoic acid receptor (RARα,
β and γ) family of nuclear receptor
proteins. To date, a number of crystal structures of natural
and synthetic ligands complexed to their target proteins have
been solved, providing molecular level snap-shots of ligand
binding. However, a deeper understanding of receptor and ligand
flexibility and conformational freedom is required to develop
stable and effective ATRA analogues for clinical use.
Therefore, we have used molecular modelling techniques to
define RAR interactions with ATRA and two synthetic analogues,
EC19 and EC23, and compared their predicted biochemical
activities to experimental measurements of relative ligand
affinity and recruitment of coactivator proteins. A
comprehensive molecular docking approach that explored the
conformational space of the ligands indicated that ATRA is able
to bind the three RAR proteins in a number of conformations
with one extended structure being favoured. In contrast the
biologically-distinct isomer, 9-cis-retinoic acid (9CRA),
showed significantly less conformational flexibility in the RAR
binding pockets. These findings were used to inform docking
studies of the synthetic retinoids EC23 and EC19, and their
respective methyl esters. EC23 was found to be an excellent
mimic for ATRA, and occupied similar binding modes to ATRA in
all three target RAR proteins. In comparison, EC19 exhibited an
alternative binding mode which reduces the strength of key
polar interactions in RARα/γ but is
well-suited to the larger RARβ binding pocket. In
contrast, docking of the corresponding esters revealed the loss
of key polar interactions which may explain the much reduced
biological activity. Our computational results were
complemented using an in vitro binding assay based on FRET
measurements, which showed that EC23 was a strongly binding,
pan-agonist of the RARs, while EC19 exhibited specificity for
RARβ, as predicted by the docking studies. These
findings can account for the distinct behaviour of EC23 and
EC19 in cellular differentiation assays, and additionally, the
methods described herein can be further applied to the
understanding of the molecular basis for the selectivity of
different retinoids to RARα, β and
γ.
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2013-01-31 | BIOMD0000000629 | BioModels
Project description:Many different molecular mechanisms have been suggested to be associated with PML-RAR dependent transformation of haematopoietic progenitors. Here, we investigated the role of PML-RAR and RXR in the organization of epigenetic structures at a genome-wide level. We identified 2722 high confidence PML-RAR binding sites in the leukemic model cell line NB4 and found PML-RAR colocalization with RXR to the vast majority of these binding regions. Importantly, these results could be corroborated and extended in primary blast cells of two APL patients. Through genome-wide epigenetic studies we show that treatment with pharmacological doses of all-trans retinoic acid ATRA induces global alterations in active H3 acetylation and repressive H3K27me3, H3K9me3 and DNA methylation chromatin modifications. However at the PML-RAR/RXR binding sites, ATRA only induces changes in H3 acetylation. These H3 acetylation alterations triggered by the loss of PML-RAR/RXR binding affect H3 acetylation and RNA polymerase II occupancy at nearby genes. Our results suggest that PML-RAR/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for haematopoietic differentiation, RAR signaling and epigenetic control is crucial to the transforming potential of PML-RAR/RXR.
2009-12-17 | GSE18886 | GEO
Project description:Early life exposure to endocrine disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ) and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ versus RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators (‘rexinoids’, 4204 and TBT) attenuate glucose uptake, blunt expression of the anti-diabetic hormone adiponectin, and fail to down-regulate pro-inflammatory and pro-fibrotic transcripts as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.
2018-06-19 | GSE115946 | GEO
Project description:Nucleotide-binding oligomerization domain 2 (Nod2) signaling is critical for human health.To figure out the clinical relevance of NOD2 ligands, the investigators plan to evaluate the change of NOD2 ligands in inflammatory bowel diseases (IBD), CRC, atherosclerotic cardiovascular disease (ACVD), and type 2 diabetes mellitus (DM2 ).
| 2380440 | ecrin-mdr-crc
Project description:We defined the RARα interactome in the MDA-MB453 breast cancer cell line genetically engineered to over-express an N-terminally tagged version of the nuclear retinoic acid receptor. Twenty eight nuclear proteins which interact with RARα and whose interaction is stimulated or reduced by the pan-RAR ligand, all-trans retinoic acid (ATRA) were identified. Given the potential significance of the S100A3 calcium-binding protein in the control of tumor progression, we focused our attention on this factor. Using the two models represented by the ATRA-sensitive SKBR3 and MCF7 breast cancer cell lines characterized by constitutive expression of S100A3 and RARα, we demonstrate that the endogenous forms of S100A3 and RARα interact in physiological conditions. The interaction of S100A3 with RARα is cell context independent and it is observed not only in breast cancer but also in acute promyelocytioc leukemia (APL) cells, characterized by expression of the RARα-derived PML-RARα oncogene, which is the product of the t(15:17) chromosomal translocation. S100A3 interacts directly and specifically with RARα and PML-RARα, being unable to bind other members of the RAR/RXR family of retinoid nuclear receptors. The interaction surface maps to the carboxyl-terminal region of the RARα ligand binding domain. Binding of S100A3 to RARα and PML-RARα controls the constitutive and ATRA-dependent degradation of the two receptors. Silencing of the S100A3 gene decreases the amounts of RARα in breast SK-BR-3 and lung A549 cancer cells, rendering them more refractory to the anti-proliferative action of ATRA. In SK-BR-3 cells, this effect is accompanied by a decrease in the lactogenic/differentiating action of ATRA. In APL-derived NB4 cells, S100A3 knock-down reduces the amounts of both RARα and PML-RARα. Contemporaneous down-regulation of the two receptors is associated with an increase in the basal and ATRA-induced expression of many granulocytic differentiation markers. Opposite on RARα and PML-RARα levels as well as ATRA induced differentiation markers are observed upon over-expression of S100A3 in NB4 cells.
2019-12-18 | PXD008761 | Pride
Project description:Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but the mechanisms underlying their action and synergy remain elusive. ATRA inhibits APL, breast and liver cancers by targeting isomerase Pin1, a master regulator of oncogenic signaling. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, similar to Pin1 CRISPR knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic Pin1 inhibition by ATO and ATRA offers an attractive approach to combating breast and other cancers.
2018-10-16 | PXD010224 | Pride
Project description:A rexinoid, targretin (TRG) and two retinoids, 9-cis retinoic acid (9cRA) and 4-hydroxyphenylretinamide (4HPR) were examined for their effects on gene expression in rat mammary gland, liver, and lung tissues. The chemopreventive effects of these agents have largely been attributed to their ability to interact with retinoic acid receptors (RAR) and/or retinoid X-receptors (RXR). TRG interacts with the RXR receptors. 9cRA interacts with both the RAR and RXR receptors, while 4HPR has a moderate affinity primarily for RAR gamma. Based on previously performed mammary chemoprevention studies, TRG (150mg/Kg diet), 9cRA (100 mg/Kg diet), and 4HPR (792 mg/Kg diet), were administrated to rats continually in their diet for 7 days. Tissue - and agent - specific expression differences were determined by comparing tissues from treated rats with those form rats administered a control diet. There were significantly more changes seen associated with TRG than 9cRA or 4HPR. Only a limited number of expression changes were found with 4HPR treatment. For each organ, TRG and 9cRA treated tissues clustered closely together, whereas 4HPR treated tissues clustered with the tissues from the control diet group. In contrast to 9cRA treatment, TRG treatment altered genes that involved fatty acid metabolism and modulation of various cytochromes P450 in the liver clearly demonstrating the very disparate nature of these two retinoids. These expression signatures could provide useful pharmacodynamic biomarkers for retinoidsâ treatment and chemoprevention. Experiment Overall Design: Agent : The 3 agents were obtained from NCI Chemical Repository (Bethesda, MD), Targretin, 9-cis retinoic acid, and 4-hydroxyphenylretinamide. Experiment Overall Design: Rat :Female Sprague-Dawley rats were used (Harlan Sprague-Dawley, Inc. Indianapolis, IN) Experiment Overall Design: Treatment: Starting at 100 days of age, the rats received treatment of TRG (60 mg/kg BW, gavage), 9cRA (100 mg/kg diet), or 4HPR (782 mg/kg diet) for 7 days. At the end of the 7-day treatment, normal mammary gland, liver and lung tissues were collected.
2007-11-06 | E-GEOD-3952 | biostudies-arrayexpress
Project description:Examination of three retinoid X receptor (RXR) agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)] showed that all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglyceride levels. Agents were administered in diets to female Sprague-Dawley rats. Liver RNA was isolated and microarrayed on the Affymetrix GeneChip Rat Exon 1.0 ST array. Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists. Genes in specific modules were changed by one, two, or all three agonists. An interactome analysis assessed the effects on genes that heterodimerize with known nuclear receptors. For proliferator-activated receptor α/RXR-activated genes, the strongest response was TRG > 4-Me-UAB30 > UAB30. Many liver X receptor/RXR-related genes (e.g., Scd-1 and Srebf1, which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30- but not UAB30-treated livers. Minimal expression changes were associated with retinoic acid receptor or vitamin D receptor heterodimers by any of the agonists. UAB30 unexpectedly and uniquely activated genes associated with the aryl hydrocarbon hydroxylase (Ah) receptor (Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1). Based on the Ah receptor activation, UAB30 was tested for its ability to prevent dimethylbenzanthracene (DMBA)-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective. Gene expression changes were determined by reverse transcriptase-polymerase chain reaction in rat livers treated with Targretin for 2.3, 7, and 21 days. These showed similar gene expression changes at all three time points, arguing some steady-state effect. Different patterns of gene expression among the agonists provided insight into molecular differences and allowed one to predict certain physiologic consequences of agonist treatment. Three treatments were administered. Four samples were obtained for each of the 3 treatment groups for a total of 12 treatment samples. Four control samples were analyzed.
2014-05-14 | E-GEOD-57638 | biostudies-arrayexpress