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

Natalia Novac^*,1, Daniela Baus^*, Anja Dostert^*,2 and Thorsten Heinzel^,3

^* Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany; and

Institute of Biochemistry and Biophysics, Friedrich-Schiller-University, Jena, Germany

³Correspondence: Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Philosophenweg 12, Jena 07743, Germany. E-mail: t.heinzel{at}uni-jena.de

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 NFB binding site. GR down-regulates fasL promoter by competing with NFB for binding to the common response element. Thus, fasL is the first gene described whose repression by GR is mediated by sterical occlusion of NFB DNA binding. This type of repression represents an additional mechanism for the GR-NFB mutual antagonism.—Novac, N., Baus, D., Dostert, A., Heinzel, T. Competition between glucocorticoid receptor and NFB for control of the human FasL promoter.

Key Words: nGRE • AICD • inflammation • glucocorticoid receptor • cis-repression

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