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The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

ABSTRACT: The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

PROVIDER: PRJNA1022499 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26229700.fastq.gz	Fastqsanger.gz
	SRR26229701.fastq.gz	Fastqsanger.gz
	SRR26229702.fastq.gz	Fastqsanger.gz
	SRR26229703.fastq.gz	Fastqsanger.gz
	SRR26229704.fastq.gz	Fastqsanger.gz

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Similar Datasets

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

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. Our previous studies 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

Transcription profiling of F9 teratocarcinoma sublines characterized by the presence or absence of the RAR gamma nuclear retinoic acid receptor treated with trans retinoic acid and the novel retinoid, ST1926

Project description:Effect of all trans retinoic acid and the novel retinoid, ST1926, on the profile of gene expression in F9 teratocarcinoma sublines characterized by the presence or absence of the RAR gamma nuclear retinoic acid receptor

2005-12-31 | E-MEXP-361 | biostudies-arrayexpress

Connecting ligand-induced retinoid X receptor structural dynamics to rexinoid agonist potency

Project description:Retinoid X receptors (RXR) are nuclear transcription factors that partner with other nuclear receptors to regulate numerous physiological processes. Although RXR represents a valid therapeutic target, only a few RXR-specific ligands (rexinoids) have been identified, in part due to the lack of clarity on how rexinoids selectively modulate RXR response. Previously, we showed that rexinoid UAB30 potentiates all-trans-retinoic acid (ATRA) signaling in human keratinocytes by stimulating ATRA biosynthesis. Here, we examined the mechanism of action of next-generation rexinoids UAB110 and UAB111 that are more potent in vitro than UAB30 and the FDA-approved Targretin. Both UAB110 and UAB111 enhanced ATRA signaling in human organotypic epithelium at a 50-fold lower concentration than UAB30. This was consistent with the 2- to 5- fold greater increase in ATRA in skin rafts treated with UAB110/111 versus UAB30. Furthermore, at 0.2 µM, UAB110/111 increased the expression of ATRA genes up to 16-fold stronger than Targretin. The less toxic and more potent UAB110 also induced more changes in differential gene expression than Targretin. The hydrogen deuterium exchange mass spectrometry analysis showed that both ligands reduced the dynamics of the ligand-binding pocket but also induced unique dynamic responses that were indicative of higher affinity binding relative to UAB30, especially for Helix 3. UAB110 binding also showed increased dynamics towards the dimer interface through the Helix 8 and Helix 9 regions. These data suggest that UAB110 and UAB111 are potent activators of RAR: RXR signaling pathways but accomplish activation through different molecular responses to ligand binding.

2023-01-11 | GSE199381 | GEO

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

Project description: Not available

| S-EPMC10984533 | biostudies-literature

Connecting ligand-induced retinoid X receptor structural dynamics to rexinoid agonist potency

Project description:Connecting ligand-induced retinoid X receptor structural dynamics to rexinoid agonist potency

| PRJNA819485 | ENA

Transcript levels in CCE WT and RARgamma knockout murine embryonic stem cells treated with either all-trans retinoic acid (8 and 24 hr) or with vehicle control

Project description:Retinoic acid receptors (RARs) ?, ?, and ? heterodimerize with Retinoid X receptors (RXR) ?, ?, and ? and bind the cis-acting response elements known as RAREs to execute the biological functions of retinoic acid during mammalian development. RAR? mediates the anti-proliferative and apoptotic effects of retinoids in certain tissues and cancer cells, such as melanoma and neuroblastoma cells. Furthermore, ablation of RAR? enhanced the tumor incidence of Ras transformed keratinocytes and was associated with resistance to retinoid mediated growth arrest and apoptosis. We used microarray analysis to identify genes, which upon 8 or 24 hr of treatment with all-trans retinoic acid display differential expression in RAR? knockout (RAR?KO) murine embryonic stem cells relative to CCE WT cells. We demonstrate that following RA treatment the majority of inducible transcripts are present at lower levels in RAR?KO ES cells compared to WT ES cells. Murine embryonic stem cells (WT and RAR?KO) were treated with either all-trans retinoic acid (up to 24 hr) or with vehicle control (EtOH).

2012-12-31 | E-GEOD-43221 | biostudies-arrayexpress

Gene expression profiling on bronchoalveolar lavage (BAL) cells treated with all-trans-retinoic acid (ATRA)

Project description:All-trans retinoic acid (ATRA) is a potent retinoid, which has been used successfully in different clinical settings as a potential drug to treat COPD and emphysema. In alveolar macrophages, ATRA selectively down-regulates MMP-9 and up-regulates TIMP-1 expression. In the present study, we analyzed additional genes modulated by ATRA by performing mRNA expression array on alveolar macrophages after treatment with ATRA.

2010-09-04 | GSE23704 | GEO

Analysis of retinoid targets in chick embryo wing buds

Project description:Chick wing buds at Hamburger and Hamilton stage 20 were treated with DMSO, all trans retinoic acid or synthetic retinoid EC23 via ion-exchange beads implanted into the wing buds. The anterior third of treated wing buds of surviving embryos were removed 24 hours after treatment by microdissection and pooled to prepare RNA extracts for microarray analysis.

2020-12-31 | E-MTAB-2545 | biostudies-arrayexpress

RNA-seq profiling of rexinoid responsive gene expression during early myogenic differentiation

Project description:While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor, promotes the specification and differentiation of skeletal muscle lineage. Here, we examine a genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between retinoid X receptor signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation.

2017-09-13 | GSE94560 | GEO

Retinoic acid effect on cardiac mitochondria

Project description:Using H9C2 cardiomyoblasts, we have shown that all-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A, affects mitochondrial dynamics at 10nM concentration. The low dose ATRA stimulates the expression of nuclear retinoid receptors and induces mechanisms that are protective against severe point damage caused by laser irradiation at the mitochondrial level. To determine the protective effect of ATRA against photodamage, we used the proteomic analysis based on liquid chromatography and mass spectrometry (LC-MS/MS) to compare the abundancies of proteins between control and ATRA-treated cardiomyoblasts.

2022-02-23 | PXD026967 | Pride

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