It has become increasingly clear that glucocorticoid signalling not only comprises the binding of the glucocorticoid receptor (GR) to its response element (GRE), but also involves indirect regulation glucocorticoid-responsive genes by regulating or interacting with other transcription factors. In addition, they can directly regulate gene expression by binding to negative glucocorticoid response elements (nGREs), to simple GREs, to GREs, or to GREs and GRE half sites (GRE1/2s) that are part of a regulatory unit. A response unit allows a higher level of glucocorticoid induction than simple GREs and, in addition, allows the integration of tissue-specific information with the glucocorticoid response. Presumably, the complexity of such a glucocorticoid response unit (GRU) depends on the number of pathways that integrate at this unit. Because GRUs are often located at distant sites relative to the transcription-start site, the GRU has to find a way to communicate with the basal-transcription machinery. We propose that the activating signal of a distal enhancer can be relayed onto the transcription-initiation complex by coupling elements located proximal to the promoter.
"The activated GR is transported into the nucleus to regulate the expression levels of inflammatory and sugar dysmetabolism-related genes, including nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), TNF-α, glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) (13). Its ability to regulate inflammatory gene expression has led to the GR becoming the primary target for the development of anti-inflammatory agents (14). As a typical first-line anti-inflammatory agent, the clinical application of Dex is limited due to severe side-effects, which are induced by the transcriptional activation of GR (15,16). "
[Show abstract][Hide abstract] ABSTRACT: The present study aimed to identify a new selective glucocorticoid receptor (GR) ligand for the treatment of chronic inflammation in type 2 diabetes mellitus. The IN Cell Analyzer 1000 platform was employed to screen for compounds that may promote GR nuclear translocation. A mammalian two-hybrid system and transactivation assay-were used to analyze the selected GR ligands and evaluate their activities for GR transcription and the recruitment of co-activators. A novel selective GR ligand, compound Q40, was identified that was able to promote GR nuclear translocation in a short period of time. It increased the ability of GR to recruit co-activators in a concentration-dependent manner, but had no positive effect on GR transcriptional activity. In conclusion, an increase in the expression levels of gluconeogeneic genes, induced by the transcriptional activation of GR, is the predisposing factor most commonly associated with the side-effects of glucocorticoids. The results suggest that compound Q40 is a ligand of the GR and exerts an agonistic action on the recruitment of co-activators without sugar dysmetabolism-related side-effects. Thus, compound Q40 has the potential to be used as an anti-inflammatory adjuvant therapy with minimal side-effects in patients with type 2 diabetes mellitus.
Experimental and therapeutic medicine 10/2014; 8(4):1111-1114. DOI:10.3892/etm.2014.1860 · 1.27 Impact Factor
"Many, but not all , of the effects of the glucocorticoids are mediated by GR-dependent control of gene transcription . In the ligand-unbound state, the GR is localized to the cell cytosol; upon ligand binding, the GR translocates to the nucleus . "
[Show abstract][Hide abstract] ABSTRACT: Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice.
PLoS ONE 04/2014; 9(4):e96200. DOI:10.1371/journal.pone.0096200 · 3.23 Impact Factor
"in regions that promote stress recovery (Bale et al., 2000; Coste et al., 2000), including the LS (Victoria et al. 2013, unpublished data). Given that corticosterone-GR complexes transcriptionally regulate the central expression of CRFRs (Schoneveld et al., 2004), such changes are expected. "
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