Impaired Smad7-Smurf–mediated negative regulation of TGF-β signaling in scleroderma fibroblasts
Copyright policy )Impaired Smad7-Smurf–mediated negative regulation of TGF-β signaling in scleroderma fibroblasts
The principal effect of TGF-beta1 on mesenchymal cells is its stimulation of ECM synthesis. Previous reports indicated the significance of the autocrine TGF-beta loop in the pathogenesis of scleroderma. In this study, we focused on Smad7 and Smurfs, principal molecules in the negative regulation of TGF-beta signaling, to further understand the autocrine TGF-beta loop in scleroderma. Scleroderma fibroblasts exhibited increased Smad7 levels compared with normal fibroblasts in vivo and in vitro. Smad7 constitutively formed a complex with the TGF-beta receptors, and the inhibitory effect of Smad7 on the promoter activity of human alpha2(I) collagen and 3TP-lux was completely impaired in scleroderma fibroblasts. Furthermore, the protein stability of TGF-beta receptor type I was significantly increased in scleroderma fibroblasts compared with normal fibroblasts. There was no significant difference in Smurf1 and Smurf2 levels between normal and scleroderma fibroblasts, and the transiently overexpressed Smurf1 and/or Smurf2 did not affect TGF-beta receptor type I protein levels in scleroderma fibroblasts. These results indicate that the impaired Smad7-Smurf-mediated inhibitory effect on TGF-beta signaling might contribute to maintaining the autocrine TGF-beta loop in scleroderma fibroblasts. To our knowledge, this is the first report of a disturbed negative regulation of TGF-beta signaling in fibrotic disorders.
- University of Tokyo Japan
Blotting, Western, Immunoblotting, Oligonucleotides, Fibroblasts, Blotting, Northern, Immunohistochemistry, Precipitin Tests, Collagen Type I, DNA-Binding Proteins, Gene Expression Regulation, Microscopy, Fluorescence, Humans, RNA, Collagen, RNA, Messenger, Phosphorylation, Receptors, Transforming Growth Factor beta, Cells, Cultured, Densitometry, Plasmids
Blotting, Western, Immunoblotting, Oligonucleotides, Fibroblasts, Blotting, Northern, Immunohistochemistry, Precipitin Tests, Collagen Type I, DNA-Binding Proteins, Gene Expression Regulation, Microscopy, Fluorescence, Humans, RNA, Collagen, RNA, Messenger, Phosphorylation, Receptors, Transforming Growth Factor beta, Cells, Cultured, Densitometry, Plasmids
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).207 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!