DOI: 10.1101/gad.827900. The glucocorticoid receptor inhibits NFκB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain

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

10.1101/gad.827900

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

Abstract

Glucocorticoids repress NFκB-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 NFκB 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 NFκB in vitro and that the ZBR is sufficient to associate with RelA bound at NFκB response elements in vivo. Moreover, we demonstrate in vivo and in vitro that GR does not disrupt DNA binding by NFκB. In transient transfections, we found that the GR ligand binding domain is essential for repression of NFκB but not for association with it and that GR can repress an NFκB 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 NFκB-activated transcription. As expected, we found that the inflammatory signal TNFα 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.

Bibliography

Nissen, R. M., & Yamamoto, K. R. (2000). The glucocorticoid receptor inhibits NFÎºB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes & Development, 14(18), 2314â2329.

Authors 2

Robert M. Nissen (first)
Keith R. Yamamoto (additional)

References 131 Referenced 436

10.1038/sj.bjp.0702613
10.1101/gad.12.22.3541
10.1038/387049a0
10.1016/0092-8674(85)90117-5
10.1073/pnas.95.23.13543
10.1073/pnas.94.26.14300
10.1126/science.270.5234.286
10.1128/MCB.16.10.5772 / Mol. Cell. Biol. / Mad proteins contain a dominant transcription repression domain. by Ayer (1996)
10.1016/0092-8674(88)90382-0
10.1126/science.3140380
10.1146/annurev.immunol.14.1.649
{'key': '2021111419232379000_14.18.2314.12', 'first-page': '330', 'article-title': 'Genetic analysis of the repetitive carboxyl-terminal domain of the largest subunit of mouse RNA polymerase II.', 'volume': '8', 'author': 'Bartolomei', 'year': '1988', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Genetic analysis of the repetitive carboxyl-terminal domain of the largest subunit of mouse RNA polymerase II. by Bartolomei (1988)
Birnstiel M.L. (1988) Structure and function of major and minor small nuclear ribonucleoprotein particles. (Springer Verlag, New York, NY). (10.1007/978-3-642-73020-7)
10.1126/science.281.5373.60 / Science / Going the distance: A current view of enhancer action. by Blackwood (1998)
10.1101/gad.12.11.1638
10.1002/j.1460-2075.1991.tb04994.x / EMBO J. / Cytoplasmic retention, DNA binding and processing of the NF-κ B p50 precursor are controlled by a small region in its C-terminus. by Blank (1991)
10.1093/nar/27.22.4399
10.1128/MCB.16.8.4349 / Mol. Cell. Biol. / Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. by Braunstein (1996)
10.1074/jbc.271.32.19612
10.1210/me.9.4.401
10.1038/34956
10.1016/S0092-8674(00)80516-4
10.1101/gad.9.13.1586
10.1074/jbc.275.15.10719
10.1101/gad.13.12.1540
10.1128/MCB.15.6.2983 / Mol. Cell. Biol. / KIN28 encodes a C-terminal domain kinase that controls mRNA transcription in Saccharomyces cerevisiae but lacks cyclin-dependent kinase-activating kinase (CAK) activity. by Cismowski (1995)
10.1111/j.1749-6632.1999.tb07628.x
10.1101/gad.12.21.3343
10.1073/pnas.94.25.13504
10.1093/nar/11.5.1475
10.1111/j.1749-6632.1999.tb07618.x
10.1101/gad.14.4.422 / Genes & Dev. / The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies. by Freeman (2000)
10.1038/373303a0
10.1146/annurev.immunol.16.1.225
10.1038/325365a0
10.1101/gad.11.13.1640
10.1038/38664
10.1128/MCB.19.8.5652 / Mol. Cell. Biol. / Transcription factor TFIIH is required for promoter melting in vivo. by Guzman (1999)
10.1002/jlb.56.5.559 / J. Leukoc. Biol. / Essential involvement of interleukin-8 (IL-8) in acute inflammation. by Harada (1994)
10.1016/S0092-8674(00)80214-7
10.1093/emboj/16.15.4698
10.1038/42750
10.1038/387043a0
10.1016/S1097-2765(00)80112-4
10.1016/S1097-2765(00)80468-2
10.1016/S0014-5793(96)01397-X
10.1016/S0021-9258(19)38489-3 / J. Biol. Chem. / Mapping the HSP90 binding region of the glucocorticoid receptor. by Howard (1990)
10.1074/jbc.272.7.4149
10.1074/jbc.271.11.6217
10.1126/science.288.5470.1418
10.1038/368466a0
10.1002/j.1460-2075.1992.tb05283.x / EMBO J. / Interference between pathway-specific transcription factors: Glucocorticoids antagonize phorbol ester-induced AP-1 activity without altering AP-1 site occupation in vivo. by Konig (1992)
10.1101/gad.12.3.331
10.4049/jimmunol.153.1.153 / J. Immunol. / Synergistic transcriptional activation of the IL-8 gene by NF-κ B p65 (RelA) and NF-IL-6. by Kunsch (1994)
10.1038/21239
10.1016/S0092-8674(00)80215-9
10.1002/j.1460-2075.1993.tb06197.x / EMBO J. / Promoter analysis of the gene encoding the I κ B-α/MAD3 inhibitor of NF-κ B: Positive regulation by members of the rel/NF-κ B family. by Le Bail (1993)
10.1038/30770
{'key': '2021111419232379000_14.18.2314.59', 'first-page': '149', 'article-title': 'CTD kinase large subunit is encoded by CTK1, a gene required for normal growth of Saccharomyces cerevisiae.', 'volume': '1', 'author': 'Lee', 'year': '1991', 'journal-title': 'Gene Expr.'} / Gene Expr. / CTD kinase large subunit is encoded by CTK1, a gene required for normal growth of Saccharomyces cerevisiae. by Lee (1991)
10.1038/31860
10.1101/gad.8.23.2842
10.1074/jbc.275.20.14923
10.1074/jbc.272.34.21467
10.1128/MCB.18.3.1467 / Mol. Cell. Biol. / Repression of TFIIH transcriptional activity and TFIIH-associated cdk7 kinase activity at mitosis. by Long (1998)
{'key': '2021111419232379000_14.18.2314.65', 'first-page': '3446', 'article-title': 'Interaction of GAL4 and GAL80 gene regulatory proteins in vitro.', 'volume': '7', 'author': 'Lue', 'year': '1987', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Interaction of GAL4 and GAL80 gene regulatory proteins in vitro. by Lue (1987)
10.1038/352497a0
10.1128/MCB.15.5.2839 / Mol. Cell. Biol. / GAL4 interacts with TATA-binding protein and coactivators. by Melcher (1995)
10.1126/science.278.5339.860
10.1016/0968-0004(91)90168-U
10.1016/S0092-8674(00)81821-8
10.1074/jbc.274.32.22127
{'key': '2021111419232379000_14.18.2314.72', 'first-page': '674', 'article-title': 'Molecular analysis of the inhibition of interleukin-8 production by dexamethasone in a human fibrosarcoma cell line.', 'volume': '75', 'author': 'Mukaida', 'year': '1992', 'journal-title': 'Immunology'} / Immunology / Molecular analysis of the inhibition of interleukin-8 production by dexamethasone in a human fibrosarcoma cell line. by Mukaida (1992)
10.1016/S0021-9258(17)36831-X / J. Biol. Chem. / Novel mechanism of glucocorticoid-mediated gene repression. Nuclear factor-κ B is target for glucocorticoid-mediated interleukin 8 gene repression. by Mukaida (1994)
10.1038/19789
10.1016/S0092-8674(00)80218-4
10.1046/j.1432-1327.1998.2540081.x / Eur. J. Biochem. / Effect of dexamethasone on interleukin-1β-(IL-1β)-induced nuclear factor-κB (NF-κB) and κB-dependent transcription in epithelial cells. by Newton (1998)
10.1016/0092-8674(87)90517-4
10.1038/370075a0
10.1006/meth.1996.0407
10.1038/347298a0
10.1038/22350
10.1074/jbc.271.39.24151
10.1038/384375a0
10.1016/S1097-2765(00)80181-1
10.1074/jbc.274.39.27823
10.1101/gad.13.24.3198
10.1002/j.1460-2075.1987.tb02654.x / EMBO J. / Two signals mediate hormone-dependent nuclear localization of the glucocorticoid receptor. by Picard (1987)
10.1016/0092-8674(88)90122-5
10.1128/MCB.20.8.2629-2634.2000
10.1128/MCB.20.8.2718-2726.2000
10.1038/19783
10.1073/pnas.91.2.752
10.1016/S0021-9258(18)99966-7 / J. Biol. Chem. / Down-modulation of interleukin-6 gene expression by 17 β-estradiol in the absence of high affinity DNA binding by the estrogen receptor. by Ray (1994)
10.1016/0968-0004(96)10050-5
10.1002/j.1460-2075.1987.tb02369.x / EMBO J. / Functional dissection of the hormone and DNA binding activities of the glucocorticoid receptor. by Rusconi (1987)
10.1038/17141
10.1038/335563a0
10.1126/science.270.5234.283
10.1128/MCB.15.2.943 / Mol. Cell. Biol. / Characterization of mechanisms involved in transrepression of NF-κ B by activated glucocorticoid receptors. by Scheinman (1995)
10.1101/gad.3.10.1590
10.1073/pnas.92.24.11259
10.1074/jbc.270.13.7219
10.1242/dev.124.11.2191 / Development / Transcriptionally repressed germ cells lack a subpopulation of phosphorylated RNA polymerase II in early embryos of Caenorhabditis elegans and Drosophila melanogaster. by Seydoux (1997)
10.1128/MCB.19.11.7828 / Mol. Cell. Biol. / The Gal3p-Gal80p-Gal4p transcription switch of yeast: Gal3p destabilizes the Gal80p-Gal4p complex in response to galactose and ATP. by Sil (1999)
10.1101/gad.5.5.827
10.1128/jvi.56.1.135-143.1985 / J. Virol. / Regulation of cytomegalovirus gene expression: Alpha and beta promoters are trans activated by viral functions in permissive human fibroblasts. by Spaete (1985)
10.1101/gad.10.10.1271
10.1128/MCB.15.9.4971 / Mol. Cell. Biol. / Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-κ B and C/EBP β. by Stein (1995)
10.1126/science.8096091
10.1016/S1097-2765(00)80131-8
10.1016/0968-0004(96)10046-3
10.1126/science.272.5260.408
10.1006/dbio.1998.8940
10.1101/gad.2.6.718
10.1074/jbc.273.12.6769
10.1146/annurev.bi.63.070194.002315
10.1165/ajrcmb/8.3.340 / Am. J. Respir. Cell Mol. Biol. / Glucocorticoid-mediated repression of intercellular adhesion molecule-1 expression in human monocytic and bronchial epithelial cell lines. by van de Stolpe (1993)
10.1016/S0021-9258(17)37586-5 / J. Biol. Chem. / 12-O-tetradecanoylphorbol-13-acetate- and tumor necrosis factor α-mediated induction of intercellular adhesion molecule-1 is inhibited by dexamethasone. Functional analysis of the human intercellular adhesion molecular-1 promoter. by van de Stolpe (1994)
10.1093/emboj/17.2.507
10.1093/genetics/140.4.1223 / Genetics / Construction and analysis of yeast RNA polymerase II CTD deletion and substitution mutations. by West (1995)
10.1074/jbc.272.35.22278
10.1210/me.12.3.355
10.1126/science.278.5339.866
{'key': '2021111419232379000_14.18.2314.124', 'first-page': '1', 'article-title': 'Multilayered control of intracellular receptor function.', 'volume': '91', 'author': 'Yamamoto', 'year': '1995', 'journal-title': 'Harvey Lect.'} / Harvey Lect. / Multilayered control of intracellular receptor function. by Yamamoto (1995)
10.1101/sqb.1998.63.587
10.1093/emboj/17.17.5161
10.1073/pnas.94.5.1721
10.1101/gad.7.8.1584
10.1146/annurev.bi.64.070195.002533
10.1016/S0092-8674(00)80216-0
10.1016/S1097-2765(00)80066-0

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 8 p.m.)
Deposited	2 years, 4 months ago (April 23, 2023, 2:43 a.m.)
Indexed	1 week, 6 days ago (Aug. 19, 2025, 6:51 a.m.)
Issued	24 years, 11 months ago (Sept. 15, 2000)
Published	24 years, 11 months ago (Sept. 15, 2000)
Published Online	24 years, 11 months ago (Sept. 15, 2000)
Published Print	24 years, 11 months ago (Sept. 15, 2000)

Funders 0

None

BibTeX

@article{Nissen_2000, title={The glucocorticoid receptor inhibits NFκB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain}, volume={14}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.827900}, DOI={10.1101/gad.827900}, number={18}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Nissen, Robert M. and Yamamoto, Keith R.}, year={2000}, month=sep, pages={2314–2329} }

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  "abstract": "<jats:p>Glucocorticoids repress NF\u03baB-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\u2013protein interactions with NF\u03baB 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 NF\u03baB in vitro and that the ZBR is sufficient to associate with RelA bound at NF\u03baB response elements in vivo. Moreover, we demonstrate in vivo and in vitro that GR does not disrupt DNA binding by NF\u03baB. In transient transfections, we found that the GR ligand binding domain is essential for repression of NF\u03baB but not for association with it and that GR can repress an NF\u03baB 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 NF\u03baB-activated transcription. As expected, we found that the inflammatory signal TNF\u03b1 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.</jats:p>",
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      "volume": "14",
      "author": "Freeman",
      "year": "2000",
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      "author": "Guzman",
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      "volume": "56",
      "author": "Harada",
      "year": "1994",
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      "volume": "265",
      "author": "Howard",
      "year": "1990",
      "journal-title": "J. Biol. Chem."
    },
    {
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      "author": "Konig",
      "year": "1992",
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      "volume": "153",
      "author": "Kunsch",
      "year": "1994",
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      "volume": "12",
      "author": "Le Bail",
      "year": "1993",
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      "author": "Lee",
      "year": "1991",
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      "volume": "18",
      "author": "Long",
      "year": "1998",
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      "volume": "7",
      "author": "Lue",
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      "author": "Melcher",
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      "author": "Mukaida",
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      "volume": "269",
      "author": "Mukaida",
      "year": "1994",
      "journal-title": "J. Biol. Chem."
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      "volume": "254",
      "author": "Newton",
      "year": "1998",
      "journal-title": "Eur. J. Biochem."
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      "volume": "6",
      "author": "Picard",
      "year": "1987",
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      "author": "Ray",
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      "author": "Sil",
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      "volume": "56",
      "author": "Spaete",
      "year": "1985",
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    },
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      "author": "Stein",
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      "volume": "8",
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