How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering

Abstract

The activity of the glucocorticoid receptor (GR), a nuclear receptor transcription factor belonging to subclass 3C of the steroid/thyroid hormone receptor superfamily, is typically triggered by glucocorticoid hormones. Apart from driving gene transcription via binding onto glucocorticoid response elements in regulatory regions of particular target genes, GR can also inhibit gene expression via transrepression, a mechanism largely based on protein:protein interactions. Hereby GR can influence the activity of other transcription factors, without contacting DNA itself. GR is known to inhibit the activity of a growing list of immune-regulating transcription factors. Hence, GCs still rule the clinic for treatments of inflammatory disorders, notwithstanding concomitant deleterious side effects. Although patience is a virtue when it comes to deciphering the many mechanisms GR uses to influence various signaling pathways, the current review is testimony of the fact that groundbreaking mechanistic work has been accumulating over the past years and steadily continues to grow.

Keywords: ACC1; AF; AP-1; BRG1; C/EBPβ; CBP; CCAAT/enhancer binding protein β; CDK; CRH; ChIP; Cross-talk; DBD; DEX; DHS; DNA-binding domain; DNase I hypersensitive sites; DUSP1; ERK; FAS; GBS; GC; GC response element; GC-induced leucine zipper; GILZ; GPAT; GR; GR binding sequence; GRE; GRIP1; Glucocorticoid receptor; Glucocorticoids; H; HDAC; Hsp; IFN; IRF; ISGF3; IκB; LBD; MAP kinase kinase; MAP kinase phosphatase 1; MAPK; MKK; MKP-1; MMTV; MR; MSK; N-terminal transactivation domain; NF-AT; NF-κB; NF1; NGFI-B; NLSs; NTD; OTF1; PEPCK; PIC; PKA; PKB; POMC; PPAR; RA; RNA pol II; RNA polymerase II; RXR; SMRT; SRC-1; STAT; Smad; TATA-binding protein; TBP; TF; TLR; TNF; Transactivation; Transcription factor; Transrepression; acetyl co(-enzyme) A carboxylase 1; activation function; activator protein 1; brahma-related gene 1; cAMP response element (CRE) binding protein (CREB)-binding protein; chromatin immunoprecipitation; corticotropin-releasing hormone; cyclin-dependent kinase; dexamethasone; dual-specificity phosphatase 1; extracellular signal-regulated kinase; fatty acid synthase; glucocorticoid; glucocorticoid receptor; glucocorticoid receptor interacting protein 1; glycerol-3-phosphate O-acyltransferase; heat shock protein; histone; histone deacetylase; homolog of drosophila ‘mothers against decapentaplegic’; inhibitor of NF-κB; interferon; interferon regulatory factor; interferon-stimulated gene factor 3; ligand-binding domain; luc; luciferase; mineralocorticoid receptor; mitogen- and stress-activated protein kinase; mitogen-activated protein kinase; mouse mammary tumor virus; nerve growth factor-induced clone B; nuclear factor 1; nuclear factor of activated T cell; nuclear factor-κB; nuclear localization sequences; pTEFb; peroxisome proliferator-activated receptor; phosphoenolpyruvate carboxykinase; positive transcription elongation factor b; pre-initiation complex; pro-opiomelanocortin; protein kinase A; protein kinase B; redirected from cognate transcription factor octamer 1; retinoic acid; retinoid X receptor; signal transducer and activator of transcription; silencing mediator of retinoic acid and thyroid hormone receptors; steroid receptor coactivator 1; toll-like receptor; transcription factor; tumor necrosis factor.