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Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein.

Publication ,  Journal Article
Yingling, JM; Datto, MB; Wong, C; Frederick, JP; Liberati, NT; Wang, XF
Published in: Mol Cell Biol
December 1997

Members of the Smad family of proteins are thought to play important roles in transforming growth factor beta (TGF-beta)-mediated signal transduction. In response to TGF-beta, specific Smads become inducibly phosphorylated, form heteromers with Smad4, and undergo nuclear accumulation. In addition, overexpression of specific Smad combinations can mimic the transcriptional effect of TGF-beta on both the plasminogen activator inhibitor 1 (PAI-1) promoter and the reporter construct p3TP-Lux. Although these data suggest a role for Smads in regulating transcription, the precise nuclear function of these heteromeric Smad complexes remains largely unknown. Here we show that in Mv1Lu cells Smad3 and Smad4 form a TGF-beta-induced, phosphorylation-dependent, DNA binding complex that specifically recognizes a bipartite binding site within p3TP-Lux. Furthermore, we demonstrate that Smad4 itself is a DNA binding protein which recognizes the same sequence. Interestingly, mutations which eliminate the Smad DNA binding site do not interfere with either TGF-beta-dependent transcriptional activation or activation by Smad3/Smad4 cooverexpression. In contrast, mutation of adjacent AP1 sites within this context eliminates both TGF-beta-dependent transcriptional activation and activation in response to Smad3/Smad4 cooverexpression. Furthermore, concatemerized AP1 sites, in isolation, are activated by Smad3/Smad4 cooverexpression and, to a certain extent, by TGF-beta. Taken together, these data suggest that the Smad3/Smad4 complex has at least two separable nuclear functions: it forms a rapid, yet transient sequence-specific DNA binding complex, and it potentiates AP1-dependent transcriptional activation.

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Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

December 1997

Volume

17

Issue

12

Start / End Page

7019 / 7028

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Transcriptional Activation
  • Transcription Factor AP-1
  • Trans-Activators
  • Smad4 Protein
  • Smad3 Protein
  • Signal Transduction
  • Promoter Regions, Genetic
  • Polymerase Chain Reaction
  • Plasminogen Activator Inhibitor 1
 

Citation

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Yingling, J. M., Datto, M. B., Wong, C., Frederick, J. P., Liberati, N. T., & Wang, X. F. (1997). Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol Cell Biol, 17(12), 7019–7028. https://doi.org/10.1128/MCB.17.12.7019
Yingling, J. M., M. B. Datto, C. Wong, J. P. Frederick, N. T. Liberati, and X. F. Wang. “Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein.Mol Cell Biol 17, no. 12 (December 1997): 7019–28. https://doi.org/10.1128/MCB.17.12.7019.
Yingling JM, Datto MB, Wong C, Frederick JP, Liberati NT, Wang XF. Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol Cell Biol. 1997 Dec;17(12):7019–28.
Yingling, J. M., et al. “Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein.Mol Cell Biol, vol. 17, no. 12, Dec. 1997, pp. 7019–28. Pubmed, doi:10.1128/MCB.17.12.7019.
Yingling JM, Datto MB, Wong C, Frederick JP, Liberati NT, Wang XF. Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol Cell Biol. 1997 Dec;17(12):7019–7028.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

December 1997

Volume

17

Issue

12

Start / End Page

7019 / 7028

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Transcriptional Activation
  • Transcription Factor AP-1
  • Trans-Activators
  • Smad4 Protein
  • Smad3 Protein
  • Signal Transduction
  • Promoter Regions, Genetic
  • Polymerase Chain Reaction
  • Plasminogen Activator Inhibitor 1