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TNF-U+03B1 inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile
Tijdschriftbijdrage - Tijdschriftartikel
Ondertitel:TNF-alpha inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile
Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the therapeutic effects, including the antiinflammatory ones of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a problem in the management of inflammatory diseases and can be congenital as well as acquired. The strong proinflammatory cytokine TNF-alpha (TNF) induces an acute form of GCR, not only in mice, but also in several cell lines: e.g., in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-stimulated direct GR-dependent gene up-and down-regulation. We report that TNF has a significant and broad impact on this transcriptional performance of GR, but no impact on nuclear translocation, dimerization, or DNA binding capacity of GR. Proteome-wide proximitymapping (BioID), however, revealed that the GR interactome was strongly modulated by TNF. One GR cofactor that interacted significantly less with the receptor under GCR conditions is p300. NF kappa B activation and p300 knockdown both reduced direct transcriptional output of GR whereas p300 overexpression and NF kappa B inhibition reverted TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis was supported by FRET studies. This mechanism of GCR opens avenues for therapeutic interventions in GCR diseases.
Tijdschrift: Proceedings of the National Academy of Sciences of the United States of America
Pagina's: 12942 - 12951
Jaar van publicatie:2019