![]() This finding is explained by functional interactions of the GR with other transcription factors such as AP1, CREB, C/EBP, octamer binding factors, STAT5 and NF-κB. Some genes lacking GREs or nGREs in their promoters can still be affected by GCs. Upon binding as a homodimer to the so-called glucocorticoid-response elements (GREs) or negative GREs (nGREs) it can induce or repress the transcription of target genes. Once in the nucleus, the GR can utilize several different mechanisms in order to influence gene expression. Heat shock protein 90 acts as a chaperone and allows binding of the hormone, which then leads to the nuclear translocation of the GR complex. Among those is the glucocorticoid receptor (GR), which in its resting state is associated with heat shock proteins and one p59 immunophilin molecule in the cytoplasm of cells. This is achieved by binding of the hormone to transcription factors belonging to the family of steroid hormone receptors. The physiological and therapeutic effects of steroid hormones and glucocorticoids (GCs) rely on direct posttranscriptional and pharmacological effects and, more importantly, on their ability to influence gene expression. The structural requirements for the various functions of glucocorticoids are discussed. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. ![]() ![]() All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. ![]() Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. ![]()
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