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

Autor:	Melo N; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Belyaeva OV; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., 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, Florida, USA., 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, Florida, USA., Yu J; Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA., Pilli N; Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA., Yang Z; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Klyuyeva AV; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA., Elmets CA; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; Birmingham VA Medical Center, Birmingham, Alabama, USA., Atigadda V; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA., Muccio DD; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Kane MA; Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA., 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, Florida, USA., Kedishvili NY; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: nkedishvili@uab.edu., Renfrow MB; O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: renfrow@uab.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Jan; Vol. 299 (1), pp. 102746. Date of Electronic Publication: 2022 Nov 24.
DOI:	10.1016/j.jbc.2022.102746
Abstrakt:	Retinoid X receptors (RXRs) 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, in part 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 organotypic epidermis 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. Additionally, our 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 RXR-RAR signaling pathways but accomplish activation through different molecular responses to ligand binding. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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