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

Author:

Belyaeva Olga V.,Klyuyeva Alla V.ORCID,Vyas AnshORCID,Berger Wilhelm K.ORCID,Halasz Laszlo,Yu Jianshi,Atigadda Venkatram R.,Slay Aja,Goggans Kelli R.ORCID,Renfrow Matthew B.,Kane Maureen A.,Nagy Laszlo,Kedishvili Natalia Y.ORCID

Abstract

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.

Funder

UAB O’Neil Comprehensive Cancer Center

National Cancer Institute

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of Arthritis and Musculoskeletal and Skin Diseases

University of Maryland, School of Pharmacy

University of Maryland, School of Pharmacy Mass Spectrometry Center

Publisher

Public Library of Science (PLoS)

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