A new function of glucocorticoid receptor: regulation of mRNA stability

Abstract

It has long been thought that glucocorticoid receptor (GR) functions as a DNA-binding transcription factor in response to its ligand (a glucocorticoid) and thus regulates various cellular and physiological processes. It is also known that GR can bind not only to DNA but also to mRNA; this observation points to the possible role of GR in mRNA metabolism. Recent data revealed a molecular mechanism by which binding of GR to target mRNA elicits rapid mRNA degradation. GR binds to specific RNA sequences regardless of the presence of a ligand. In the presence of a ligand, however, the mRNA-associated GR can recruit PNRC2 and UPF1, both of which are specific factors involved in nonsense-mediated mRNA decay (NMD). PNRC2 then recruits the decapping complex, consequently promoting mRNA degradation. This mode of mRNA decay is termed “GR-mediated mRNA decay” (GMD). Further research demonstrated that GMD plays a critical role in chemotaxis of immune cells by targeting CCL2 mRNA. All these observations provide molecular insights into a previously unappreciated function of GR in posttranscriptional regulation of gene expression. [BMB Reports 2015; 48(7): 367-368]

UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond

“…Glucocorticoid (GC) receptor (GR) is a DNA-binding transcription factor that belongs to the nuclear receptor superfamily and regulates various biological and physiological processes (Oakley and Cidlowski 2011;Santos et al 2011;Vandevyver et al 2012). Although it has long been appreciated that GR targets DNA, several studies have revealed that GR also functions as an RNA-binding protein to elicit rapid degradation of target substrates (Dhawan et al 2007(Dhawan et al , 2012Kino et al 2010;Ishmael et al 2011;Cho et al 2015;Park et al 2015Park et al , 2016 in a process called GR-mediated mRNA decay (GMD) (Table 1; Fig. 3).…”

“…Third, GMD is a ligand-inducible mRNA decay pathway. GC treatment is sufficient for eliciting efficient GMD, as long as GMD substrates contain GR-occupied GR-binding sites (Cho et al 2015;Park et al 2015Park et al , 2016. GMD manifests additional interesting features.…”

The emerging role of RNA modifications in the regulation of mRNA stability

“…2) 36 . HRSP12 has been identified as a cellular factor involved in glucocorticoid receptormediated mRNA decay [43][44][45][46] . The RNase P/MRP complex has been characterized as an endoribonuclease that cleaves long noncoding RNAs and mRNAs, as well as precursor forms of 5.8 S rRNA and tRNA [47][48][49] .…”

Glucocorticoid receptor action in metabolic and neuronal function

“…Rapid non-genomic actions of GR have also been described in neurons and peripheral tissues 5 . GR can also modulate mRNA splicing 6 , mRNA stability 7 , and microRNA expression and processing 8 . Thus, GR controls gene expression directly as a transcription factor and indirectly by stimulating signaling pathways that coalesce on GR while also shaping gene expression post-transcriptionally through effects on RNA metabolism ( Figure 1B ).…”