The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain.

By R. Nissen, Keith R. Yamamoto. Genes & Development, 2000

603 citations recorded by the source corpus.

Glucocorticoids repress NFkappaB-mediated activation of proinflammatory genes such as interleukin-8 (IL-8) and ICAM-1. Our experiments suggest that the glucocorticoid receptor (GR) confers this effect by associating through protein-protein interactions with NFkappaB bound at each of these genes. That is, we show that the GR zinc binding region (ZBR), which includes the DNA binding and dimerization functions of the receptor, binds directly to the dimerization domain of the RelA subunit of NFkappaB in vitro and that the ZBR is sufficient to associate with RelA bound at NFkappaB response elements in vivo. Moreover, we demonstrate in vivo and in vitro that GR does not disrupt DNA binding by NFkappaB. In transient transfections, we found that the GR ligand binding domain is essential for repression of NFkappaB but not for association with it and that GR can repress an NFkappaB derivative bearing a heterologous activation domain. We used chromatin immunoprecipitation assays in untransfected A549 cells to infer the mechanism by which the tethered GR represses NFkappaB-activated transcription. As expected, we found that the inflammatory signal TNFalpha stimulated preinitiation complex (PIC) assembly at the IL-8 and ICAM-1 promoters and that the largest subunit of RNA polymerase II (pol II) in those complexes became phosphorylated at serines 2 and 5 in its carboxy-terminal domain (CTD) heptapeptide repeats (YSPTSPS); these modifications are required for transcription initiation. Remarkably, GR did not inhibit PIC assembly under repressing conditions, but rather interfered with phosphorylation of serine 2 of the pol II CTD.

Subfields: Cancer Research, Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/b07c9751625db7778b83cf822540b327b4d4638f

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Citations in the corpus

Epigenetics and the biological definition of gene x environment interactions. (2010, background): “This effect involves, in part, the interaction of the glucocorticoid receptor with another protein, NFKß (e.g., Nissen & Yamamoto, 2000), which is a major participant in the activation of inflammatory responses.”
Orchestrated response: a symphony of transcription factors for gene control. (2000, background): “ChIP analysis determined that GR-dependent transcriptional interference occurred subsequent to RNA Pol II and TFIIH association with Rel A-occupied target genes at a step involving selective phosphorylation of RNA Pol II (Nissen and Yamamoto 2000).”
Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. (2005, background): “... involved in NF-κB and AP-1 activation (Auphan et al., 1995; Caelles et al., 1997; Scheinman et al., 1995a), competition for essential coactivators (Kamei et al., 1996; Sheppard et al., 1998), alternative utilization of coactivators (Kassel et al., 2004; Rogatsky et al., 2001; Scheinman et al., 1”
Peroxisome proliferator-activated receptors in inflammation control. (2001, background): “…receptor antagonizes NF- B transcriptional activity by interfering with phosphorylation of the serine-2 of the carboxy-terminal domain of the RNA polymerase II without affecting NF- B DNA-binding activities, although the glucocorticoid receptor strongly interacts with p65 (Nissen & Yamamoto 2000).”
The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease (2013, background): “GR directly binds the Jun subunit of AP1 and the p65 subunit of NF-κB and interferes with the transcriptional activation function of these two proteins (40, 41).”
Androgen receptor (AR) coregulators: an overview. (2002, background): “The suppression of NF B transcription by GR results from the prevention of pol II phosphorylation after NF B has bound to its response element and recruited the GTFs of the preinitiation complex (29, 117).”
The aryl hydrocarbon receptor complex and the control of gene expression. (2008, background): “III.”