Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Piek, E. et al.

Piek, Ju, Heyer, Escalante-Alcalde, Stewart, Weinstein, Deng, Kucherlapati, Bottinger, Roberts,

Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts.

A prominent pathway of transforming growth factor (TGF)-beta signaling involves receptor-dependent phosphorylation of Smad2 and Smad3, which then translocate to the nucleus to activate transcription of target genes. To investigate the relative importance of these two Smad proteins in TGF-beta1 signal transduction, we have utilized a loss of function approach, based on analysis of the effects of TGF-beta1 on fibroblasts derived from mouse embryos deficient in Smad2 (S2KO) or Smad3 (S3KO). TGF-beta1 caused 50% inhibition of cellular proliferation in wild-type fibroblasts as assessed by [(3)H]thymidine incorporation, whereas the growth of S2KO or S3KO cells was only weakly inhibited by TGF-beta1. Lack of Smad2 or Smad3 expression did not affect TGF-beta1- induced fibronectin synthesis but resulted in markedly suppressed induction of plasminogen activator inhibitor-1 by TGF-beta1. Moreover, TGF-beta1- mediated induction of matrix metalloproteinase-2 was selectively dependent on Smad2, whereas induction of c-fos, Smad7, and TGF-beta1 autoinduction relied on expression of Smad3. Investigation of transcriptional activation of TGF-beta-sensitive reporter genes in the different fibroblasts showed that activation of the (Smad binding element)(4)-Lux reporter by TGF-beta1 was dependent on expression of Smad3, but not Smad2, whereas activation of the activin response element-Lux reporter was strongly suppressed in S2KO fibroblasts but, on the contrary, enhanced in S3KO cells. Our findings indicate specific roles for Smad2 and Smad3 in TGF-beta1 signaling.[1]

References

Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. Piek, E., Ju, W.J., Heyer, J., Escalante-Alcalde, D., Stewart, C.L., Weinstein, M., Deng, C., Kucherlapati, R., Bottinger, E.P., Roberts, A.B. J. Biol. Chem. (2001) [Pubmed]

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