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(Received for publication, May 21, 1997, and in revised form, June 23, 1997)
From the Department of Medical Nutrition, Karolinska Institute,
Huddinge University Hospital,
Novum F60, S-141 86 Huddinge, Sweden
Glucocorticoids inhibit NF-
Volume 272, Number 34,
Issue of August 22, 1997
pp. 21467-21472
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
REPRESSION OF RelA TRANSACTIVATION
B signaling by
interfering with the NF-B transcription factor RelA. Previous
studies have identified the DNA-binding domain (DBD) in the
glucocorticoid receptor (GR) as the major region responsible for this
repressive activity. Using GR mutants with chimeric DBDs the repressive
function was found to be located in the C-terminal zinc finger. As
predicted from these results the mineralocorticoid receptor that
contains a C-terminal zinc finger identical to that of the GR was also able to repress RelA-dependent transcription. Mutation of a
conserved arginine or a lysine in the second zinc finger of the GR DBD
(Arg-488 or Lys-490 in the rat GR) abolished the ability of GR to
inhibit RelA activity. In contrast, C-terminal zinc finger GR mutants with mutations in the dimerization box or mutations necessary for full
transcriptional GR activity were still able to repress RelA-dependent transcription. In addition, we found that
the steroid analog ZK98299 known to induce GR transrepression of AP-1
had no inhibitory effect on RelA activity. In summary, these results demonstrate that the inhibition of NF-B by glucocorticoids involves two critical amino acids in the C-terminal zinc finger of the GR.
Furthermore, the results from the use of mineralocorticoid receptor and
anti-glucocorticoids suggest that the mechanisms for GR-mediated
repression of NF-B and AP-1 are different.
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