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PMID: 10652273 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA.

Genes & development ·Vol. 14 ·No. 2 ·2000-01-15 ·Pages 187-97

Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, Böttinger EP

Abstract

A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-beta (TGF-beta) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor kappaB (NF-kappaB/RelA) is necessary for the inhibition of TGF-beta-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-alpha (TNF-alpha). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-beta receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-beta/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-kappaB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-alpha and interleukin-1beta (IL-1beta, NF-kappaB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-beta/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-kappaB/RelA.

MeSH Terms
3T3 Cells Animals COS Cells DNA-Binding Proteins/antagonists & inhibitors,genetics,physiology Ligases/metabolism,physiology Mice Mice, Mutant Strains NF-kappa B/metabolism,physiology Receptors, Transforming Growth Factor beta/antagonists & inhibitors Signal Transduction/physiology Smad7 Protein Trans-Activators/antagonists & inhibitors,genetics,physiology Transcription, Genetic Transforming Growth Factor beta/antagonists & inhibitors,physiology Tumor Necrosis Factor-alpha/physiology
Chemicals
DNA-Binding Proteins NF-kappa B Receptors, Transforming Growth Factor beta Smad7 Protein Smad7 protein, mouse Trans-Activators Transforming Growth Factor beta Tumor Necrosis Factor-alpha Ligases guanosine 3',5'-polyphosphate synthetases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Bitzer M
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461 USA.
von Gersdorff G
Liang D
Dominguez-Rosales A
Beg A A
Rojkind M
Böttinger E P
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
Published
2000-01-15
Pages
187-97
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316349
Subset
IM
Grants
NIDDK NIH HHS · R01 DK056077 · United States
NIAAA NIH HHS · R01 AA010541 · United States
NIDDK NIH HHS · DK56077-01 · United States
NIAAA NIH HHS · AA10541 · United States
NIAAA NIH HHS · R01 AA009231 · United States
NIAAA NIH HHS · AA09231 · United States
External Links
PubMed source PMC Full Text View journal details
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