Mechanisms of transcriptional regulation by glucocorticoids (adapted from M Karin ). Liganded GRs (ovals with patches) regulate transcription by direct binding to DNA elements (GREs) or by binding to other transcription factors (tethering). GRE-regulated and NF-κB/AP-1-regulated promoters are shown schematically with single binding sites; typically, there may be one or several sites. Interference with the activity of AP-1 (open and dark ovals) or NF-κB (open and dark squares) after tethering could be a direct effect on the factors' function, or it could be an interaction with coactivators or components of the TIC. AP-1 = activator protein-1; GR = glucocorticoid receptor; GRE = glucocorticoid response element; NF-κB = nuclear factor-κB; TIC = transcriptional initiation complex.