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  • The classical genomic effects of

    2022-01-15

    The classical genomic effects of GR come about through ligand-bound GR homodimerizing in the nucleus and via direct binding to GREs on the target genes, bringing about transcriptional activation or repression. Examples of target genes up-regulated by activated GR include genes encoding β2-adrenergic receptors (Barnes, 2010) mitogen-activated protein kinase phosphatase-1 (MPK-1) (Kassel et al., 2001), serum glucocorticoid-regulated kinase 1 (SGK1) (Itani et al., 2002), the gene encoding glucocorticoid-induced leucine zipper (GILZ) (Wang et al., 2004), β-arrestin-1 (Oakley et al., 2012), tristetraproline (TTP) (Smoak and Cidlowski, 2006) and importantly, genes known to play a role in glucose and fat metabolism (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (PEPCK) in the liver (van Raalte et al., 2009), and fatty fmoc-osu synthase (FAS), acetyl co (enzyme) A (ACC), SCD-1–3, and glycerol-3-phospate O-acetyltransferase (GPAT3-4) in adipocytes (Ratman et al., 2013)). Genes repressed include osteocalcin (Barnes, 2011), β-arrestin 2 (Oakley et al., 2012) and the GR gene itself (NR3C1) (Ramamoorthy and Cidlowski, 2013). In summary, DNA in the form of GREs can both positively and negatively regulate target gene expression through modulating GR function. Alternatively, GR can modulate target gene expression by binding either to GRE containing variable base sequencing or by binding to composite GREs. In the case of composite GREs, the target gene has binding sites for GREs as well as other transcription factors (Kadmiel and Cidlowski, 2013). ‘Tethering’ of GREs represents yet another way that transcriptional modification of GR target genes may come about indirectly. When there is an absence of DNA binding sites, tethering GREs can recruit other transcription factors that in turn are capable of binding GR (Oakley and Cidlowski, 2011). Unlike genomic effects that can take up to hours, non-genomic effects of GC that take only minutes have been reported. These rapid effects are thought enabled by the activation of signal transduction pathways via membrane-bound GR (e.g. the mitogen-activated protein kinase (MAPK) pathway). Other GR-independent non-genomic effects involving glucocorticoid physiochemical interactions with components of the cell membrane have also been reported in a variety of body systems (Song and Buttgereit, 2006). Phosphorylation of GR on several different serine residues by a number of kinases (e.g. by MAPK, glycogen-synthase kinase-3 (GSK-3) and casein kinase II) has been shown to occur in response to GR receptor activation produced by ligand binding (Anbalagan et al., 2012, Galliher-Beckley et al., 2011), but may also occur hormone-independently (Galliher-Beckley et al., 2011). As previously alluded to, GR undergoes SUMOylation and this occurs on lysine residues. SUMOylation has the effect of modulating specific cellular functionalities such as chromatin organization, protein stabilization and subcellular locus, and transcriptional activity. When GRα undergoes SUMOylation it becomes targeted for degradation (Oakley and Cidlowski, 2011). Acetylation in response to GC has been also been reported to involve lysine residues (494 and 495) and is coupled to reduced ability of GR to subdue the activity of nuclear factor kappa B (NF-κB), that along with AP-1 (comprising C-jun and C-fos proteins) is a known pro-inflammatory transcription factor (Barnes, 2009) (Smoak and Cidlowski, 2004). More recently, acetylation of lysines in the hinge region of the GR containing a KXKK motif by the circadian rhythm transcription factor “clock” (deemed to be an important component of the “biological clock”) has been reported as repressing transcriptional activity of GR, and may act as a local counter-regulatory mechanism to the actions of GC (Kino and Chrousos, 2011). Finally, alterations to GR ubiquitination and to at least one identified ubiquitin ligase also serve to post-translationally modulate GR activity (Wallace and Cidlowski, 2001) (Wang and De Franco, 2005)