p65-activated histone acetyltransferase activity is repressed by glucocorticoids: mifepristone fails to recruit HDAC2 to the p65-HAT complex.

Glucocorticoids acting through their specific receptor can either enhance or repress gene transcription. Dexamethasone represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor expression through a combination of direct inhibition of p65-associated histone acetyltransferase (HAT) activity and by recruiting histone deacetylase 2 (HDAC2) to the p65-HAT complex. Here we show that ...
mifepristone, a glucocorticoid receptor partial agonist, has no ability to induce gene expression but represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor release by 50% maximally. Mifepristone was able to inhibit p65-associated HAT activity to the same extent as dexamethasone but failed to inhibit the natural promoter to an equal extent due to an inability to recruit HDAC2 to the p65-associated HAT complex. These data suggest that the maximal repressive actions of glucocorticoids require recruitment of HDAC2 to a p65-HAT complex. These data also suggest that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases.
Mesh Terms:
Acetylation, Acetyltransferases, Anti-Inflammatory Agents, Non-Steroidal, Blotting, Western, Cell Nucleus, Chromatin, Dexamethasone, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Glucocorticoids, Granulocyte-Macrophage Colony-Stimulating Factor, Histone Acetyltransferases, Histone Deacetylase 2, Histone Deacetylases, Histones, Hormone Antagonists, Humans, Immunohistochemistry, Inflammation, Interleukin-1, Lysine, Mifepristone, NF-kappa B, Precipitin Tests, Protein Binding, Receptors, Glucocorticoid, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Saccharomyces cerevisiae Proteins, Transcription Factor RelA, Transcription, Genetic, Tumor Cells, Cultured
J. Biol. Chem.
Date: Aug. 10, 2001
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