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GR dimerization and the impact of GR dimerization on GR protein stability and half-life

dc.contributor.authorLouw, Annen_ZA
dc.contributor.editorLibert, Claudeen_ZA
dc.date.accessioned2019-07-23T05:51:18Z
dc.date.available2019-07-23T05:51:18Z
dc.date.issued2019-07-17
dc.identifier.citationLouw, A. 2019. GR dimerization and the impact of GR dimerization on GR protein stability and half-life. Frontiers in Immunology, 10:1693, doi:10.3389/fimmu.2019.01693en_ZA
dc.identifier.issn1664-3224 (online)
dc.identifier.otherdoi:10.3389/fimmu.2019.01693
dc.identifier.urihttp://hdl.handle.net/10019.1/106321
dc.descriptionCITATION: Louw, A. 2019. GR dimerization and the impact of GR dimerization on GR protein stability and half-life. Frontiers in Immunology, 10:1693, doi:10.3389/fimmu.2019.01693.en_ZA
dc.descriptionThe original publication is available at https://www.frontiersin.orgen_ZA
dc.descriptionPublication of this article was funded by the Stellenbosch University Open Access Funden_ZA
dc.description.abstractPharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy. Dimerization of the GR is an integral step in glucocorticoid signaling and has been identified as a possible molecular site to target for drug development of anti-inflammatory drugs with an improved therapeutic index. Most of the current understanding regarding the role of GR dimerization in GC signaling derives for dimerization deficient mutants, although the role of ligands biased toward monomerization has also been described. Even though designing for loss of dimerization hasmostly been applied for reduction of side-effect profile, designing for loss of dimerization may also be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. GC-induced resistance affects up to 30% of users and is due to a reduction in the GR functional pool. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR dimerization prevents autologous down-regulation of the receptor through modulation of interactions with components of the UPS and post-translational modifications (PTMs), such as phosphorylation, which prime the GR for degradation. Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore. However, potential drawbacks to this approach should be considered as well as the advantages and disadvantages in chronic vs. acute treatment regimes.en_ZA
dc.description.urihttps://www.frontiersin.org/articles/10.3389/fimmu.2019.01693/full
dc.format.extent15 pages : illustrationsen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherFrontiers Mediaen_ZA
dc.subjectGlucocorticoids -- Receptors -- Dimerizationen_ZA
dc.subjectAcquired glucocorticoid resistanceen_ZA
dc.subjectGlucocorticoids -- Receptors -- Protein stabilityen_ZA
dc.subjectGlucocorticoids -- Receptors -- Effect of drugs onen_ZA
dc.titleGR dimerization and the impact of GR dimerization on GR protein stability and half-lifeen_ZA
dc.typeArticleen_ZA
dc.description.versionPublisher's versionen_ZA
dc.rights.holderAuthors retain copyrighten_ZA


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