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      Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.

      Nature

      Amino Acid Sequence, Animals, COS Cells, Cell Line, Culture Techniques, DNA-Binding Proteins, analysis, physiology, Feedback, Gene Expression Regulation, Genes, Reporter, Humans, Mice, Molecular Sequence Data, Phosphorylation, Signal Transduction, Smad7 Protein, Trans-Activators, Transfection, Transforming Growth Factor beta, antagonists & inhibitors, biosynthesis, Xenopus, Xenopus Proteins

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          Abstract

          TGF-beta signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. The activated TGF-beta receptor induces phosphorylation of two such proteins, Smad2 and Smad3, which form hetero-oligomeric complex(es) with Smad4/DPC4 that translocate to the nucleus, where they then regulate transcriptional responses. However, the mechanisms by which the intracellular signals of TGF-beta are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6. Transfection of Smad7 blocks responses mediated by TGF-beta in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-beta signalling. Smad7 associates stably with the TGF-beta receptor complex, but is not phosphorylated upon TGF-beta stimulation. TGFbeta-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-beta rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-beta responses.

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          Journal
          9335507
          10.1038/39369

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