PUBLICATION
Smad7 antagonizes TGF-{beta} signaling in the nucleus by interfering with functional Smad-DNA complex formation
- Authors
- Zhang, S., Fei, T., Zhang, L., Zhang, R., Chen, F., Ning, Y., Han, Y., Feng, X.H., Meng, A., and Chen, Y.G.
- ID
- ZDB-PUB-070427-20
- Date
- 2007
- Source
- Molecular and cellular biology 27(12): 4488-4499 (Journal)
- Registered Authors
- Meng, Anming, Zhang, Lixia
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- COS Cells
- Carcinoma, Hepatocellular/pathology
- Cell Line
- Cell Line, Tumor
- Cell Nucleus/metabolism*
- Chlorocebus aethiops
- DNA/metabolism*
- DNA-Binding Proteins
- Gene Deletion
- Genes, Reporter
- HeLa Cells
- Humans
- Liver Neoplasms/pathology
- Luciferases/analysis
- Luciferases/metabolism
- Protein Binding
- Protein Structure, Tertiary
- RNA Interference
- Signal Transduction*
- Smad7 Protein/chemistry
- Smad7 Protein/genetics
- Smad7 Protein/metabolism*
- Transforming Growth Factor beta1/antagonists & inhibitors*
- PubMed
- 17438144 Full text @ Mol. Cell. Biol.
Citation
Zhang, S., Fei, T., Zhang, L., Zhang, R., Chen, F., Ning, Y., Han, Y., Feng, X.H., Meng, A., and Chen, Y.G. (2007) Smad7 antagonizes TGF-{beta} signaling in the nucleus by interfering with functional Smad-DNA complex formation. Molecular and cellular biology. 27(12):4488-4499.
Abstract
Smad7 plays an essential role in the negative feedback regulation of TGF-beta signaling by inhibiting TGF-beta signaling at the receptor level. It can interfere with the binding to type I receptors and thus activation of R-Smads or recruit E3 ubiquitin ligase Smurf to receptors and thus targeting them for degradation. Here, we report that Smad7 was predominantly localized in the nucleus of Hep3B cells. The targeted expression of Smad7 in the nucleus conferred a superior inhibitory activity on TGF-beta signaling as determined by reporter assay in mammalian cells and by its effect on zebrafish embryogenesis. Furthermore, Smad7 repressed Smad3/4-, Smad2/4- and Smad1/4-enhanced the reporter gene expression, indicating that Smad7 can function independently of type I receptors. Oligonucleotide precipitation assay revealed that Smad7 can specifically bind to the Smad responsive element via its MH2 domain, and the DNA-binding activity was further confirmed in vivo with the promoter of PAI-1, a TGF-beta target gene, by chromatin immunoprecipitation. Finally, we provided evidence that Smad7 disrupts the formation of the TGF-beta-induced functional Smad-DNA complex. Our findings suggest that Smad7 inhibits TGF-beta signaling in the nucleus in a novel mechanism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping