Competition between glucocorticoid receptor and NFkappaB for control of the human FasL promoter.
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.
Novac
Natalia
N
Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany.
Baus
Daniela
D
Dostert
Anja
A
Heinzel
Thorsten
T
D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D019281:Dimerization; D015536:Down-Regulation; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D048069:Tumor Necrosis Factors; D003907:Dexamethasone