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Competition between glucocorticoid receptor and NFκB for control of the human FasL promoter
Author(s) -
Novac Natalia,
Baus Daniela,
Dostert Anja,
Heinzel Thorsten
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5457com
Subject(s) - glucocorticoid receptor , transactivation , fas ligand , transcription factor , psychological repression , response element , biology , microbiology and biotechnology , glucocorticoid , promoter , transcription (linguistics) , gene expression , gene , apoptosis , programmed cell death , genetics , immunology , linguistics , philosophy
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 NFκB binding site. GR down‐regulates fasL promoter by competing with NFκB for binding to the common response element. Thus, fasL is the first gene described whose repression by GR is mediated by sterical occlusion of NFkB DNA binding. This type of repression represents an additional mechanism for the GR‐ NFkB mutual antagonism.—Novac, N., Baus, D., Dostert, A., Heinzel, T. Competition between glucocorticoid receptor and NFkB for control of the human FasL promoter. FASEBJ . 20, 1074–1081 (2006)