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B (Nuclear Factor-B) and Glucocorticoid Receptor Physical Interactions and Antagonism
Molecular Endocrinology Group Laboratory of Signal Transduction National Institute of Environmental Health Sciences National Institutes of Health Research Triangle Park, North Carolina 27709-2233
Nuclear factor–
B (NF-B) and the
glucocorticoid receptor (GR) are transcription factors with opposing
actions in the modulation of immune/inflammatory responses. NF-B
induces the expression of proinflammatory genes, while GR suppresses
immune function in part by suppressing expression of the same genes.
Previously, we demonstrated that physiological antagonism between
NF-B and GR is due to a mutual transcriptional antagonism that
requires the p65 subunit of NF-B and multiple domains of GR
(1). To elucidate the mechanism(s) of NF-B p65 and GR
transcriptional antagonism, we analyzed the interactions of wild-type
p65 and p65 RHD (rel homology domain, a dominant negative mutant of p65
which lacks a transactivation domain) with GR. We show that p65RHD
blocks p65-mediated transactivation, yet does not block the repression
of GR transactivation by p65, indicating that transcriptional activity
by p65 is not required to repress GR function. Both p65 and p65 RHD
physically interact with GR, but only intact p65 represses GR-mediated
signaling, implicating the p65 transactivation domain in the
transcriptional repression of GR. To further characterize p65-GR
interactions, we examined the role of the transcriptional co-integrator
CREB binding protein (CBP) in their mutual antagonism. GR-mediated
repression of p65 transactivation and p65-mediated repression of GR
transactivation, as well as the physical interaction between NF-B
and GR, are enhanced by CBP. GR bound to the antagonist RU 486,
although transcriptionally inactive, retains the ability to repress p65
transactivation. However, CBP does not physically interact with
antagonist-bound GR and does not enhance its repressive effect on p65.
These data suggest that CBP functions as an integrator of p65/GR
physical interaction, rather than as a limiting cofactor for which p65
and GR compete.
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