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

[Display omitted] ► The pleiotropic glucocorticoid receptor deploys a multitude of mechanisms. ► Glucocorticoids can positively and negatively affect gene transcription. ► Cross-talk of glucocorticoid receptors with other transcription factors is essential. ► Glucocorticoid receptor DNA binding typically occurs, but not in all mechanisms. 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.