Role of Smad proteins in the regulation of NF-kappaB by TGF-beta in colon cancer cells.

Academic Article

Abstract

  • Nuclear factor kappa B (NF-kappaB) has been implicated in cancer cell survival. We explored the role of the TGF-beta pathway in the regulation of NF-kappaB in colon cancer cells. TGF-beta-1 treatment of the colon adenocarcinoma cell line FET-1, results in an early increase in IkappaB-alpha phosphorylation that precedes NF-kappaB nuclear translocation and DNA binding activity. Activation of the TGF-beta type I receptor is required for the TGF-beta-mediated activation of NF-kappaB. No activation of NF-kappaB is observed in a Smad4 null cell line, SW480, even though TGF-beta does result in IkappaB-alpha phosphorylation in these cells. Smad4 restores the TGF-beta-1-mediated NF-kappaB activation in SW480 cells. TGF-beta-1 treatment fails to activate NF-kappaB or phosphorylate IkappaB-alpha in FET-1 cells expressing the inhibitory Smad, Smad7. Taken together, these results suggest a role for Smad4 in the transcriptional activation of NF-kappaB, and a direct effect of Smad 7 inhibiting IkappaB-alpha phosphorylation rather than through the well-established inhibition of Smad2/3 phosphorylation with subsequent inhibition of the TGF-beta pathway.
  • Published In

    Keywords

  • Active Transport, Cell Nucleus, Activin Receptors, Type I, Animals, Cell Line, Tumor, Cell Nucleus, Colonic Neoplasms, DNA, Enzyme Activation, Epithelial Cells, Humans, I-kappa B Kinase, NF-kappa B, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad4 Protein, Smad7 Protein, Transcriptional Activation, Transforming Growth Factor beta, Transforming Growth Factor beta1
  • Digital Object Identifier (doi)

    Author List

  • Grau AM; Datta PK; Zi J; Halder SK; Beauchamp RD
  • Start Page

  • 1041
  • End Page

  • 1050
  • Volume

  • 18
  • Issue

  • 7