The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid Article Swipe
Olga V. Belyaeva
,
Alla Klyuyeva
,
Ansh Vyas
,
Wilhelm K. Berger
,
László Halász
,
Jianshi Yu
,
Venkatram R. Atigadda
,
Aja Slay
,
Kelli R. Goggans
,
Matthew B. Renfrow
,
Maureen A. Kane
,
László Nagy
,
Natalia Y. Kedishvili
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1371/journal.pone.0301447
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1371/journal.pone.0301447
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.
Related Topics
Concepts
Retinoid X receptor
Retinoic acid
Retinoid
Cell biology
Nuclear receptor
Biology
Retinoid X receptor alpha
Epidermis (zoology)
Receptor
Endogeny
Transcription factor
Biochemistry
Gene
Anatomy
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1371/journal.pone.0301447
- https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0301447&type=printable
- OA Status
- gold
- Cited By
- 1
- References
- 56
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4393392342
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4393392342Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1371/journal.pone.0301447Digital Object Identifier
- Title
-
The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acidWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-04-01Full publication date if available
- Authors
-
Olga V. Belyaeva, Alla Klyuyeva, Ansh Vyas, Wilhelm K. Berger, László Halász, Jianshi Yu, Venkatram R. Atigadda, Aja Slay, Kelli R. Goggans, Matthew B. Renfrow, Maureen A. Kane, László Nagy, Natalia Y. KedishviliList of authors in order
- Landing page
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https://doi.org/10.1371/journal.pone.0301447Publisher landing page
- PDF URL
-
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0301447&type=printableDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
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https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0301447&type=printableDirect OA link when available
- Concepts
-
Retinoid X receptor, Retinoic acid, Retinoid, Cell biology, Nuclear receptor, Biology, Retinoid X receptor alpha, Epidermis (zoology), Receptor, Endogeny, Transcription factor, Biochemistry, Gene, AnatomyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
1Total citation count in OpenAlex
- Citations by year (recent)
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2024: 1Per-year citation counts (last 5 years)
- References (count)
-
56Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W3133692232, https://openalex.org/W2927521772, https://openalex.org/W2467027766, https://openalex.org/W1999446842, https://openalex.org/W2469666886, https://openalex.org/W2098291983, https://openalex.org/W2951765624, https://openalex.org/W3164691479, https://openalex.org/W2460834770, https://openalex.org/W1240985075, https://openalex.org/W2055524611, https://openalex.org/W1529472464, https://openalex.org/W2326080135, https://openalex.org/W2336750451, https://openalex.org/W4310070104, https://openalex.org/W1927684145, https://openalex.org/W2788846071, https://openalex.org/W2470038164, https://openalex.org/W2101041635, https://openalex.org/W1989279157, https://openalex.org/W207933033, https://openalex.org/W2015071110, https://openalex.org/W2115261526, https://openalex.org/W1998607564, https://openalex.org/W2510875395, https://openalex.org/W1951724000, https://openalex.org/W2999016253, https://openalex.org/W1551998217, https://openalex.org/W129841773, https://openalex.org/W1559746628, https://openalex.org/W2033652720, https://openalex.org/W2316072378, https://openalex.org/W1996954083, https://openalex.org/W2583010607, https://openalex.org/W4235741716, https://openalex.org/W2913018331, https://openalex.org/W1563157603, https://openalex.org/W2078313611, https://openalex.org/W1999220002, https://openalex.org/W2088018249, https://openalex.org/W2133466985, https://openalex.org/W2293897234, https://openalex.org/W2044462473, https://openalex.org/W2131421001, https://openalex.org/W1603742465, https://openalex.org/W2949701230, https://openalex.org/W2003877984, https://openalex.org/W580370566, https://openalex.org/W2765333863, https://openalex.org/W1974161676, https://openalex.org/W2084893672, https://openalex.org/W3106571717, https://openalex.org/W3210626506, https://openalex.org/W2163112976, https://openalex.org/W2091846413, https://openalex.org/W4238480468 |
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| corresponding_author_ids | https://openalex.org/A5001167665, https://openalex.org/A5034766267, https://openalex.org/A5111685551, https://openalex.org/A5094300891, https://openalex.org/A5071442198, https://openalex.org/A5078738730, https://openalex.org/A5010710528, https://openalex.org/A5021209563, https://openalex.org/A5002232743, https://openalex.org/A5017338064, https://openalex.org/A5044434268, https://openalex.org/A5069095946, https://openalex.org/A5011772702 |
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| institutions_distinct_count | 13 |
| corresponding_institution_ids | https://openalex.org/I126744593, https://openalex.org/I145311948, https://openalex.org/I32389192, https://openalex.org/I4210098865 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
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| sustainable_development_goals[0].display_name | Good health and well-being |
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| citation_normalized_percentile.is_in_top_10_percent | False |