Resistance to transforming growth factor-beta occurs in the presence of normal Smad activation.

Berger DH, Feng XH, Yao J, Saha D, Beauchamp RD, Lin X
Surgery. 2002 132 (2): 310-6

PMID: 12219028 · DOI:10.1067/msy.2002.126097

BACKGROUND - Resistance to the growth inhibitory actions of transforming growth factor-beta (TGF-beta) is common in human cancers. This resistance can be a result of decreased expression of TGF-beta receptors. Downregulation of c-Myc by TGF-beta is critical for TGF-beta-mediated growth inhibition. In this study we hypothesized that decreased TGF-beta receptor expression leads to reduced Smad signaling and overexpression of c-Myc in intestinal epithelial (RIE) and transformed intestinal epithelial cells (RIE-Tr) cells.

METHODS - RIE (TGF-beta-sensitive) and RIE-Tr (TGF-beta-resistant) cells were treated with and without fetal bovine serum and TGF-beta. Western blot analysis was performed to detect levels of c-Myc, Smad2, Smad4, and phosphorylated Smad2 in RIE and RIE-Tr cells. Smad complex formation was analyzed by immunoprecipitation-coupled Western blotting.

RESULTS - c-Myc is overexpressed in RIE-Tr cells. TGF-beta-mediated downregulation of c-Myc is abrogated in RIE-Tr cells. Smad expression and activation is normal in RIE-Tr cells. We found that Smad2, Smad4, and Smad6 expression remained constant in RIE and RIE-Tr cells with or without serum or TGF-beta treatment. In addition, TGF-beta induced similar Smad2 phosphorylation and Smad complex formation in both RIE and RIE-Tr cells.

CONCLUSIONS - Our data demonstrate that Smad signaling is preserved in the face of decreased TGF-beta receptor levels. We also demonstrate that Smad signaling is not sufficient for TGF-beta-mediated c-Myc repression.

MeSH Terms (17)

Animals Cell Division Cells, Cultured DNA-Binding Proteins Down-Regulation Drug Resistance Gene Expression Intestinal Mucosa Proto-Oncogene Proteins c-myc Rats Signal Transduction Smad2 Protein Smad4 Protein Smad6 Protein Trans-Activators Transforming Growth Factor beta Transforming Growth Factor beta1

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