Competition between glucocorticoid receptor and NFκB for control of the human FasL promoter

Abstract

Glucocorticoids mediate a variety of biological effects via binding their intracellular receptor. Ligand-bound glucocorticoid receptor (GR) translocates to the nucleus and regulates gene transcription in a DNA binding-dependent or independent manner. The predominant biological effect of glucocorticoids on peripheral T cells is immunosupression via transcriptional repression of genes induced during T cell activation. Glucocorticoids have been implicated in the inhibition of activation-induced T cell apoptosis by virtue of their down-regulation of Fas ligand (fasL) expression. It is believed that FasL, similar to other cytokines, is repressed by glucocorticoids via GR interaction with other transcription factors, interfering with their transactivation ability. Here, we show that human fasL is directly regulated by GR in a DNA binding-dependent manner. A negative GR element found at position -990 in the fasL promoter binds GR in vitro as well as in the chromatin context. This negative glucocorticoid response element overlaps with a known NFkappaB binding site. GR down-regulates fasL promoter by competing with NFkappaB for binding to the common response element. Thus, fasL is the first gene described whose repression by GR is mediated by sterical occlusion of NFkappaB DNA binding. This type of repression represents an additional mechanism for the GR-NFkappaB mutual antagonism.

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

“…The GR is also able to repress transcription by DNA-based interactions with other transcription factors in composite elements, for example in Gc-mediated repression of the corticotropin-releasing hormone gene (Malkoski & Dorin 1999). Other mechanisms of repression include tethering other DNA-bound transcription factors such as in the repression of NF-kB action (Nissen & Yamamoto 2000) and via competition with a transcriptional activator for DNA-binding sites such as repression of FasL expression by NF-kB (Novac et al 2006). Observations from transgenic animals that express a dimerisation-deficient mutation of the GR suggest that a proportion of the effects of Gcs are not modulated by dimerisation-dependent DNA interactions (Reichardt & Schütz 1998).…”

Involvement of the intrinsic and extrinsic cell‐death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat‐labile enterotoxin

“…In fact, the activation-induced T-cell apoptosis, a phenomenon mediated by Fas/FasL interaction [17], is known to be inhibited in vitro by glucocorticoids through the downregulation of FasL expression in T cells [18,19]. This effect is controlled by the binding of ligand-bound glucocorticoid receptor to a negative glucocorticoid regulatory element within the fasL promoter [20,21]. This site overlaps with a NFkBbinding site, establishing a competition between ligand-bound glucocorticoid receptor and NFkB for the regulation of FasL expression [21].…”

“…This effect is controlled by the binding of ligand-bound glucocorticoid receptor to a negative glucocorticoid regulatory element within the fasL promoter [20,21]. This site overlaps with a NFkBbinding site, establishing a competition between ligand-bound glucocorticoid receptor and NFkB for the regulation of FasL expression [21]. Interestingly, the in vitro treatment of CD4 + and CD8 + T cells with the B subunit of LT induces a rapid activation and nuclear translocation of NFkB [9], which may interfere with the negative effect of glucocorticoids in the regulation of FasL expression and Fas-induced cell death of T cells.…”

Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

“…Indeed, part of the complexity of GR action on anti-inflammatory genes includes GR/NF-B antagonism at the level of gene promoters, leading to the steric occlusion of NF-B DNA binding by GR (Novac et al, 2006). Given our model of the dissociative activity of ⌬-9,11 analogs, we would expect NF-B DNA binding to be retained but GRE-mediated DNA binding to be lost, thus leading to differential regula-B C D A Fig.…”