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Vol. 14, No. 18, pp. 2314-2329, September 15, 2000
B by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain
Departments of Cellular and Molecular Pharmacology, and Biochemistry
and Biophysics, PIBS Biochemistry and Molecular Biology Program, University of
California, San Francisco, San Francisco, California 94143-0450, USA
Glucocorticoids repress NF
B-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
NFB 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 NFB in vitro and that
the ZBR is sufficient to associate with RelA bound at NFB response
elements in vivo. Moreover, we demonstrate in vivo and in vitro that GR does not disrupt DNA binding by NFB. In transient transfections, we found that the GR ligand binding domain is essential for repression of NFB but not for association with it and that GR can repress an
NFB 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 NFB-activated transcription. As expected, we found that the
inflammatory signal TNF
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.
[Key Words: Glucocorticoid receptor; transcriptional repression; intracellular receptor; RelA; chromatin; anti-inflammation]
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