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. 2021 Sep 24;10(10):2529. doi: 10.3390/cells10102529

Figure 2.

Figure 2

GC-mediated regulation of the GRα functional protein pool. Under basal physiological conditions, GRα synthesis (indicated in green) and degradation (indicated in red) occur at roughly the same rate. An increase in circulating GCs, however, disrupts the equilibrium of these processes, subsequently allowing for an increase in GRα downregulation via various mechanisms: (1) DNA methylation of the GR gene promoter inhibits the initiation of GRα gene transcription, (2) the formation of a repressive autoregulatory loop through which GC-bound GRα decreases the expression of its own nascent mRNA, by forming a long-range interaction with a NCOR1-deacetylase 3-containing repression complex, (3) the binding of miRNAs to AU-rich regions of the mRNA transcript, destabilizes mature GRα mRNA, (4) hyperphosphorylation of the receptor at Ser404 in humans, and Ser412 in mice, serves as a signal for the UPS-mediated degradation of GRα protein which occurs via (5) complex formation between GRα and several UPS enzymes. Hyperphosphorylation of the GRα refers to the phosphorylation of the receptor above that of its basal phosphorylation.