REDD1 (regulated in development and DNA damage 1) modulates the glucocorticoid receptor function in keratinocytes.
FKBP51
REDD1
glucocorticoid receptor
glucocorticoids
skin atrophy
Journal
Experimental dermatology
ISSN: 1600-0625
Titre abrégé: Exp Dermatol
Pays: Denmark
ID NLM: 9301549
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
27
05
2023
received:
25
01
2023
accepted:
02
07
2023
medline:
12
10
2023
pubmed:
24
7
2023
entrez:
24
7
2023
Statut:
ppublish
Résumé
Glucocorticoids (GCs) are widely used for the treatment of inflammatory skin diseases despite significant adverse effects including skin atrophy. Effects of GCs are mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Previously, we discovered that one of the GR target genes, REDD1, is causatively involved in skin atrophy. Here, we investigated its role in GR function using HaCaT REDD1 knockout (KO) keratinocytes. We found large differences in transcriptome of REDD1 KO and control Cas9 cells in response to glucocorticoid fluocinolone acetonide (FA): both the scope and amplitude of response were significantly decreased in REDD1 KO. The status of REDD1 did not affect GR stability/degradation during self-desensitization, and major steps in GR activation-its nuclear import and phosphorylation at activating Ser211. However, the amount of GR phosphorylated at Ser226 that may play negative role in GR signalling, was increased in the nuclei of REDD1 KO cells. GR nuclear import and transcriptional activity also depend on the composition of GR chaperone complex: exchange of chaperone FKBP51 (FK506-binding protein 5) for FKBP52 (FK506-binding protein 4) being a necessary step in GR activation. We found the increased expression and abnormal nuclear translocation of FKBP51 in both untreated and FA-treated REDD1 KO cells. Overall, our results suggest the existence of a feed-forward loop in GR signalling mediated by its target gene REDD1, which has translational potential for the development of safer GR-targeted therapies.
Substances chimiques
Glucocorticoids
0
Receptors, Glucocorticoid
0
DDIT4 protein, human
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1725-1733Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM112945
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR075049
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125366
Pays : United States
Informations de copyright
© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.
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