Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 8, Pages 3919-3924Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.8.3919
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Glucocorticoids (GCs) are used to combat inflammatory diseases. Their beneficial effect relies mainly on the inhibition of NF-kappa B-and/or AP-1-driven proinflammatory gene expression. Previously, we have shown that GCs repress tumor necrosis factor-induced IL-6 gene expression by an NF-kappa B-dependent nuclear mechanism without changing the DNA-binding capacity of NF-kappa B or the expression levels of the cytoplasmic inhibitor of NF-kappa B (1 kappa B-alpha), in the present work, we investigate the effect of GC repression on different natural and/or recombinant NF-kappa B-driven reporter gene constructs in the presence of increasing amounts of various coactivator molecules, such as CREB-binding protein (CBP), p300, and SRC-1. We found that GCs maintain their repressive capacities, irrespective of the amount of cofactor present in the cell. Similar results were obtained for the reciprocal transrepression of a GC receptor (GR) element-driven reporter gene by p65, We demonstrate that neither the expression levels of p65 and CBP nor their physical association are affected by activated CR, Using Gal4 chimeras, we show that repression by GCs is specific for p65-mediated transactivation, ruling out competition for limiting nuclear factors as the major underlying mechanism of gene repression. In addition, the transactivation potential of a point-mutated Cal4-p65 variant with a decreased CBP interaction capability is still repressed by GR. Finally, we present evidence that the specificity of GC repression on p65-driven gene expression is codetermined by the TATA box context.
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