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

Grau AM, Datta PK, Zi J, Halder SK, Beauchamp RD
Cell Signal. 2006 18 (7): 1041-50

PMID: 16288847 · DOI:10.1016/j.cellsig.2005.08.021

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.

MeSH Terms (23)

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-Serine-Threonine Kinases Protein Binding 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

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