PMID- 36436565
OWN - NLM
STAT- MEDLINE
DCOM- 20230127
LR  - 20231004
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 299
IP  - 1
DP  - 2023 Jan
TI  - Next-generation retinoid X receptor agonists increase ATRA signaling in 
      organotypic epithelium cultures and have distinct effects on receptor dynamics.
PG  - 102746
LID - S0021-9258(22)01189-9 [pii]
LID - 10.1016/j.jbc.2022.102746 [doi]
LID - 102746
AB  - 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 muM, 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.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Melo, Nathalia
AU  - Melo N
AD  - 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.
FAU - Belyaeva, Olga V
AU  - Belyaeva OV
AD  - 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.
FAU - Berger, Wilhelm K
AU  - Berger WK
AD  - 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.
FAU - Halasz, Laszlo
AU  - Halasz L
AD  - 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.
FAU - Yu, Jianshi
AU  - Yu J
AD  - Department of Pharmaceutical Sciences, University of Maryland, Baltimore, 
      Maryland, USA.
FAU - Pilli, Nagesh
AU  - Pilli N
AD  - Department of Pharmaceutical Sciences, University of Maryland, Baltimore, 
      Maryland, USA.
FAU - Yang, Zhengrong
AU  - Yang Z
AD  - 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.
FAU - Klyuyeva, Alla V
AU  - Klyuyeva AV
AD  - O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, 
      Birmingham, Alabama, USA.
FAU - Elmets, Craig A
AU  - Elmets CA
AD  - 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.
FAU - Atigadda, Venkatram
AU  - Atigadda V
AD  - O'Neil Comprehensive Cancer Center, University of Alabama at Birmingham, 
      Birmingham, Alabama, USA; Department of Dermatology, University of Alabama at 
      Birmingham, Birmingham, Alabama, USA.
FAU - Muccio, Donald D
AU  - Muccio DD
AD  - 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.
FAU - Kane, Maureen A
AU  - Kane MA
AD  - Department of Pharmaceutical Sciences, University of Maryland, Baltimore, 
      Maryland, USA.
FAU - Nagy, Laszlo
AU  - Nagy L
AD  - 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.
FAU - Kedishvili, Natalia Y
AU  - Kedishvili NY
AD  - 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.
FAU - Renfrow, Matthew B
AU  - Renfrow MB
AD  - 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.
LA  - eng
GR  - P01 CA210946/CA/NCI NIH HHS/United States
GR  - R01 AR074846/AR/NIAMS NIH HHS/United States
GR  - R01 AR076924/AR/NIAMS NIH HHS/United States
GR  - R01 DK115924/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221124
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Retinoid X Receptors)
RN  - A61RXM4375 (Bexarotene)
RN  - 0 (Ligands)
RN  - 0 (Tetrahydronaphthalenes)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Humans
MH  - Retinoid X Receptors/metabolism
MH  - Bexarotene
MH  - Ligands
MH  - *Tetrahydronaphthalenes/pharmacology
MH  - *Tretinoin/pharmacology/metabolism
MH  - Epidermis/metabolism
PMC - PMC9807999
OTO - NOTNLM
OT  - Targretin
OT  - UAB110
OT  - UAB111
OT  - UAB30
OT  - nuclear receptor
OT  - organotypic epidermis
OT  - retinoic acid
OT  - retinoid X receptor
OT  - rexinoid agonists
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2022/11/28 06:00
MHDA- 2023/01/28 06:00
PMCR- 2022/11/24
CRDT- 2022/11/27 19:23
PHST- 2022/05/11 00:00 [received]
PHST- 2022/11/15 00:00 [revised]
PHST- 2022/11/16 00:00 [accepted]
PHST- 2022/11/28 06:00 [pubmed]
PHST- 2023/01/28 06:00 [medline]
PHST- 2022/11/27 19:23 [entrez]
PHST- 2022/11/24 00:00 [pmc-release]
AID - S0021-9258(22)01189-9 [pii]
AID - 102746 [pii]
AID - 10.1016/j.jbc.2022.102746 [doi]
PST - ppublish
SO  - J Biol Chem. 2023 Jan;299(1):102746. doi: 10.1016/j.jbc.2022.102746. Epub 2022 
      Nov 24.