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

Autor: Belyaeva OV; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Klyuyeva AV; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Vyas A; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Berger WK; Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States of America., Halasz L; Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States of America., Yu J; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, United States of America., Atigadda VR; Department of Dermatology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Slay A; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Goggans KR; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Renfrow MB; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America., Kane MA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, United States of America., Nagy L; Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States of America., Kedishvili NY; Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Apr 01; Vol. 19 (4), pp. e0301447. Date of Electronic Publication: 2024 Apr 01 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0301447
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Belyaeva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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