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Vol. 14, No. 2, pp. 187-197, January 15, 2000
/SMAD signaling by NF-
B/RelA
1 Departments of Medicine, 2 Molecular Genetics
and 3 Pathology, and 4 Marion Bessin Liver Research
Center, Albert Einstein College of Medicine, Bronx, New York 10461 USA;
5 Department of Biological Sciences, Columbia University,
New York, New York 10027 USA
A number of pathogenic and proinflammatory stimuli, and the
transforming growth factor-
(TGF-) exert opposing activities in
cellular and immune responses. Here we show that the RelA subunit of
nuclear factor 
B (NF-B/RelA) is necessary for the
inhibition of TGF--induced phosphorylation, nuclear translocation,
and DNA binding of SMAD signaling complexes by tumor necrosis
factor-
(TNF-). The antagonism is mediated through up-regulation
of Smad7 synthesis and induction of stable associations between
ligand-activated TGF- receptors and inhibitory Smad7.
Down-regulation of endogenous Smad7 by expression of antisense mRNA
releases TGF-/SMAD-induced transcriptional responses
from suppression by cytokine-activated NF-B/RelA.
Following stimulation with bacterial lipopolysaccharide (LPS), or the
proinflammatory cytokines TNF- and interleukin-1 (IL-1,
NF-B/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of
suppression of TGF-/SMAD signaling by opposing stimuli
mediated through the activation of inhibitory Smad7 by NF-B/RelA.
[Key Words:
NF-B; SMADs; TGF-; signal
transduction; cytokines]
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