Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor

Abstract

Glucocorticoids (GCs) exert their anti-inflammatory andimmunosuppressive effects by inhibiting the expression of cytokines andadhesion molecules. The molecular basis of GC action lies in theircapacity to diffuse through the cell membrane and bind their cytosolicGC receptor (GR), which subsequently undergoes nuclear translocationand modulates transcriptional activation through association withpromoter elements, GC response elements (GRE). GR also antagonized theactivity of transcription factors, including NF-κB, NF-AT, and AP-1,through direct and indirect mechanisms. GCs induced the genetranscription and protein synthesis of the NF-κB inhibitor, IκB. Activated GR antagonized transcription factor activity throughprotein:protein interaction. This involved complexing with andinhibition of transcription factor binding to DNA (simple model),association with factor bound at its DNA site (compositemodel), and/or through interaction of GRE-bound GR withDNA-bound transcription factor (transmodulation model). Finally, GRcompeted with transcription factors for nuclear coactivators(competition model), including CBP and p300. Remarkably, GR did notaffect the assembly of the preinitiation complex but acted proximallyin inhibiting transcription factor activity and thus transcriptionalinitiation.