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

Wilkinson, Legh; Verhoog, Nicolette; Louw, Ann

doi:10.1038/s41598-018-32440-z

Cited by 13 publications

(28 citation statements)

References 90 publications

(151 reference statements)

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“…Accordingly, their regulation under conditions of psychological or physical stress are also unknown. In this study, we quantified protein levels of GRα, the key isoform of GR that is crucially involved in transactivation, subcellular localization and the initiation of key molecular signalling pathways 47 – 50 . We analysed Western blot data from whole tissue lysates aiming at capturing information regarding the other GR isoforms that exist (some still of unknown function).…”

Section: Discussionmentioning

confidence: 99%

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

Fennell

Busby

et al. 2020

Sci Rep

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Independent studies have observed that a paternal history of stress or trauma is associated with his children having a greater likelihood of developing psychopathologies such as anxiety disorders. This father-to-child effect is reproduced in several mouse models of stress, which have been crucial in developing a greater understanding of intergenerational epigenetic inheritance. We previously reported that treatment of C57Bl/6J male breeders with low-dose corticosterone (CORT) for 28 days prior to mating yielded increased anxiety-related behaviours in their male F1 offspring. The present study aimed to determine whether subchronic 7-day CORT treatment of male mice just prior to mating would be sufficient to induce intergenerational modifications of anxiety-related behaviours in offspring. We report that subchronic CORT treatment of male breeders reduced their week-on-week body weight gain and altered NR3C1 and CRH gene expression in the hypothalamus. There were no effects on sperm count and glucocorticoid receptor protein levels within the epididymal tissue of male breeders. Regarding the F1 offspring, screening for anxiety-related behaviours using the elevated-plus maze, light–dark box, and novelty-suppressed feeding test revealed no differences between the offspring of CORT-treated breeders compared to controls. Thus, it is crucial that future studies take into consideration the duration of exposure when assessing the intergenerational impacts of paternal health.

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Section: Discussionmentioning

confidence: 99%

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

Fennell

Busby

et al. 2020

Sci Rep

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“…Therefore, recently, it was proposed that chronic inflammatory diseases which require a long-term GC therapy would benefit from “Selective Monomer GR Agonists and Modulators” (SEMOGRAMs), since these SEMOGRAMs would avoid important side effects such as hyperglycemia that are detrimental for the patients. Recently, it was also observed that ligand-induced GR turnover leading to GCR is GR dimer dependent (220). The latter observation thus further supports the need for SEMOGRAMs for the treatment of chronic inflammation.…”

Section: Gc Therapy In Acute Vs Chronic Inflammation: Sirs and The Smentioning

confidence: 99%

A General Introduction to Glucocorticoid Biology

2019

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Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results.

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“…Recently, our laboratory investigated the hypothesis that GR dimerization may be required for homologous down-regulation of the GR by employing conditions that either promote or reduce GR dimerization (176). Promotion of GR dimerization through the use of dimerization promoting ligands, such as DEX and cortisol, induced significant down-regulation of GR wt , both transiently transfected and endogenous in HepG2 cells, while reduction of dimerization, through the use of either CpdA or GR dim , severely restricted GR turn-over.…”

Section: Impact Of Gr Dimerization On the Therapeutic Index Of Glucocmentioning

confidence: 99%

GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life

Louw

2019

Front. Immunol.

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Pharmacologically, 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 has mostly 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.

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

Cited by 13 publications

References 90 publications

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

A General Introduction to Glucocorticoid Biology

GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life

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