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- W2890143197 abstract "Abstract Glucocorticoids (GCs), acting via the glucocorticoid receptor (GRα), remain the mainstay therapeutic choice for the treatment of inflammation. However, chronic GC use, aside from generating undesirable side-effects, results in GRα down-regulation, often coupled to a decrease in GC-responsiveness, which may culminate in acquired GC resistance. The current study presents evidence for a novel role of the dimerization state of the GRα in mediating GC-mediated GRα turnover. Through comparing the effects of dimerization promoting GCs on down-regulation of a transfected human wild type GRα (hGRwt) or a dimerization deficient GRα mutant (hGRdim), we established that a loss of receptor dimerization restricts GRα turnover, which was supported by the use of the dimerization abrogating Compound A (CpdA), in cells containing endogenous GRα. Moreover, we showed that the dimerization state of the GRα influenced the post-translational processing of the receptor, specifically hyper-phosphorylation at Ser404, which influenced the interaction of GRα with the E3 ligase, FBXW7α, thus hampering receptor turnover via the proteasome. Lastly, the restorative effects of CpdA on the GRα pool, in the presence of Dex, were demonstrated in a combinatorial treatment protocol. These results expand our understanding of factors that contribute to GC-resistance and may be exploited clinically." @default.
- W2890143197 created "2018-09-27" @default.
- W2890143197 creator A5031198427 @default.
- W2890143197 creator A5034700979 @default.
- W2890143197 creator A5040777054 @default.
- W2890143197 date "2018-09-24" @default.
- W2890143197 modified "2023-10-12" @default.
- W2890143197 title "Novel role for receptor dimerization in post-translational processing and turnover of the GRα" @default.
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- W2890143197 doi "https://doi.org/10.1038/s41598-018-32440-z" @default.
- W2890143197 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6155283" @default.
- W2890143197 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30250038" @default.
- W2890143197 hasPublicationYear "2018" @default.