Novel role for receptor dimerization in post-translational processing and turnover of the GRα

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dc.contributor.authorLouw, Annen_ZA
dc.contributor.authorWilkinson, Leghen_ZA
dc.contributor.authorVerhoog, Nicoletteen_ZA
dc.date.accessioned2018-10-01T06:48:41Z
dc.date.available2018-10-01T06:48:41Z
dc.date.issued2018
dc.descriptionCITATION: Wilkinson, L., Verhoog, N. & Louw, A. 2018. Novel role for receptor dimerization in post-translational processing and turnover of the GRα. Scientific Reports, 8:14266, doi:10.1038/s41598-018-32440-z.
dc.descriptionThe original publication is available at https://www.nature.com
dc.description.abstractGlucocorticoids (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.en_ZA
dc.description.urihttps://www.nature.com/articles/s41598-018-32440-z
dc.description.versionPublisher's versionen_ZA
dc.format.extent17 pages : illustrationsen_ZA
dc.identifier.citationWilkinson, L., Verhoog, N. & Louw, A. 2018. Novel role for receptor dimerization in post-translational processing and turnover of the GRα. Scientific Reports, 8:14266, doi:10.1038/s41598-018-32440-z.en_ZA
dc.identifier.issn2045-2322 (online)
dc.identifier.otherDOI:10.1038/s41598-018-32440-z
dc.identifier.urihttp://hdl.handle.net/10019.1/104542
dc.language.isoen_ZAen_ZA
dc.publisherNatureen_ZA
dc.rights.holderScientific Reportsen_ZA
dc.subjectGlucocorticoidsen_ZA
dc.subjectGlucocorticoid -- Receptorsen_ZA
dc.subjectReceptor dimerizationen_ZA
dc.subjectTreatment of inflammationen_ZA
dc.titleNovel role for receptor dimerization in post-translational processing and turnover of the GRαen_ZA
dc.typeArticleen_ZA
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