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Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the

S Kyun Lim1, F Michael Hoffmann

  • 1McArdle Laboratory for Cancer Research and Laboratory of Genetics, University of Wisconsin, Madison, WI 53706, USA.

Proceedings of the National Academy of Sciences of the United States of America
|November 30, 2006
PubMed

Insights

Smad4 activates c-myc expression and cell growth independently of TGF-beta by binding to promoter elements. Inhibiting Smad4-LEF/TCF interaction reduces c-myc and cell proliferation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The c-myc protooncogene regulates cell proliferation.
  • Transforming growth factor-beta (TGF-beta) inhibits c-myc expression in epithelial cells.
  • Wnt ligands promote c-myc expression and cell proliferation.

Purpose of the Study:

  • To investigate the role of Smad4 in regulating c-myc expression.
  • To explore the interaction between Smad4 and Wnt signaling pathway components.
  • To determine the TGF-beta-independent functions of Smad4 in c-myc regulation.

Main Methods:

  • Peptide aptamer inhibition of Smad4-LEF/TCF binding.
  • RNA interference (RNAi) for Smad4 knockdown.
  • Analysis of c-myc promoter activity and gene expression.
  • Assessment of cell proliferation and cell death.

Main Results:

  • A peptide aptamer targeting Smad4-LEF/TCF interaction reduced c-myc expression and HepG2 cell growth.
  • Smad4 binds to the TBE1 element of the c-myc promoter, activating its activity independently of TGF-beta.
  • TGF-beta reduces Smad4 binding to TBE1, consistent with its inhibitory role.
  • Smad4 knockdown reduced c-myc levels and sensitized cells to serum deprivation-induced death.
  • Tumor-derived Smad4 mutants retained the ability to activate c-myc with LEF1.

Conclusions:

  • Smad4 possesses a novel TGF-beta-independent function in activating c-myc expression.
  • Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor (LEF/TCF) to promote c-myc expression and cell growth.
  • Targeting the Smad4-LEF/TCF interaction may offer therapeutic strategies for cancers driven by aberrant c-myc expression.

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