Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics

Melo, Nathália Caroline de Oliveira; Belyaeva, Olga V.; Berger, Wilhelm K.; Halász, László; Yu, Jianshi; Pilli, Nagesh; Yang, Zhengrong; Klyuyeva, Alla; Elmets, Craig A.; Atigadda, Venkatram R.; Muccio, Donald D.; Kane, Maureen A.; Nagy, László; Kedishvili, Natalia Y.; Renfrow, Matthew B.

doi:10.1016/j.jbc.2022.102746

Cited by 5 publications

(16 citation statements)

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“…Having established that overexpression of dnRXRα did not visibly alter epidermal histology and had a mild impact on gene expression pattern, we next asked whether the overexpression of dnRXRα would impact the response of epidermal cultures to rexinoids. Our previous studies demonstrated that both UAB30 and UAB110 markedly altered the stratification pattern of skin raft cultures [ 14 , 15 ]. In agreement with our previous results, treatment of skin rafts with 2 μM UAB30 increased the number of proliferating BrdU-positive basal keratinocytes and reduced the thickness of granular and cornified layers as indicated by the thinner and discontinuous pattern of immunostaining for filaggrin ( Fig 2 , EV+UAB30).…”

Section: Resultsmentioning

confidence: 99%

“…UAB110 was previously found to be a much more potent rexinoid than UAB30 [ 10 ], and at 0.2 μM UAB110 induced changes in stratification of skin rafts similar to those induced by 10 μM UAB30 [ 15 ]. Indeed, as reproduced in the present study, treatment of EV-rafts with 0.2 μM UAB110 resulted in more profound changes in the morphology than treatment with a ten-fold higher concentration of UAB30 (2 μM).…”

Section: Resultsmentioning

confidence: 99%

“…Retinoids were extracted from frozen skin raft samples under yellow light and quantified as described previously in detail [ 15 ]. Briefly, one skin raft per replicate was assayed.…”

Section: Methodsmentioning

confidence: 99%

“…RNA-seq analysis was carried out as described previously in detail [ 15 ]. Briefly, RNA-Seq libraries were prepared from total RNA using Ultra II RNA Sample Prep kit (New England BioLabs) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…As shown by studies from this laboratory, in a model of human organotypic epidermis, UAB30 selectively modulated the expression of genes regulated by RXR-RAR heterodimers while other RXR-mediated pathways were unaffected [ 14 ]. Interestingly, the enhanced signaling through RXR-RAR heterodimers induced by UAB30 as well as UAB110 was accompanied by an increase in the steady-state levels of all- trans -retinoic acid (ATRA) [ 14 , 15 ], the obligatory ligand for RXR-RAR transcriptional activity. It is well-established that in RXR-RAR heterodimers, the binding of rexinoid to RXR can enhance the transcriptional activity of RXR-RAR heterodimers, but only if RAR is liganded with ATRA [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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

Belyaeva,

Klyuyeva,

Vyas

et al. 2024

PLoS ONE

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Retinoids were extracted from frozen skin raft samples under yellow light and quantified as described previously in detail [ 15 ]. Briefly, one skin raft per replicate was assayed.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Belyaeva,

Klyuyeva,

Vyas

et al. 2024

PLoS ONE

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Retinoid X Receptor agonists as selective modulators of the immune system for the treatment of cancer

Leal,

Hung,

Chowdhury

et al. 2023

Pharmacology & Therapeutics

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Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein–Protein Interactions in a Yeast Two-Hybrid System

Hackney,

Broatch,

Dallal

et al. 2024

ACS Chem. Neurosci.

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Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo-and heterodimerize, and these protein−protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up-or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC 50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homoand heteropartners, driven by the physicochemical characteristics of these molecules.

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Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics

Cited by 5 publications

References 71 publications

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

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

Retinoid X Receptor agonists as selective modulators of the immune system for the treatment of cancer

Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein–Protein Interactions in a Yeast Two-Hybrid System

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