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Growth inhibitory signalling by TGFbeta is blocked in Ras-transformed intestinal epithelial cells at a post-receptor

Bo Jiang1, Jin-San Zhang, Jianguo Du

  • 1Department of Pediatrics, Children's Hospital and The Ohio State University, Columbus, OH 43205, USA.

Cellular Signalling
|May 14, 2003
PubMed

Insights

Ras-transformed intestinal cells resist transforming growth factor beta (TGFbeta) growth inhibition. This resistance, linked to reduced TGFbeta receptor II (TGFbetaRII) expression, occurs via a transcriptional mechanism affecting TIEG2 activity.

Area of Science:

  • Gastrointestinal biology
  • Cellular signaling
  • Cancer research

Background:

  • Transforming growth factor beta (TGFbeta) signaling regulates gastrointestinal epithelial cell homeostasis.
  • Loss of TGFbeta growth inhibition is common in Ras-transformed cells.
  • Reduced TGFbeta receptor II (TGFbetaRII) expression is hypothesized to cause TGFbeta resistance.

Purpose of the Study:

  • To investigate the functional significance of reduced TGFbetaRII expression in intestinal epithelial cells transformed by oncogenic Ras.
  • To analyze TGFbeta-induced signaling events downstream of TGFbetaRII in Ras-transformed cells.

Main Methods:

  • Comparison of Ras-transformed RIE-1 cells (RIE-Ras) with parental RIE-1 cells.
  • Assessment of TGFbeta-induced growth inhibition.
  • Analysis of TGFbeta receptor expression and signaling.
  • Examination of Smad2/Smad4 nuclear translocation.
  • Measurement of TIEG2 transcription factor activity.

Main Results:

  • RIE-Ras cells exhibited resistance to TGFbeta-induced growth inhibition.
  • Overexpression of TGFbetaRII or active TGFbetaRI did not restore TGFbeta sensitivity.
  • TGFbeta-mediated Smad2 phosphorylation occurred in resistant cells with low TGFbetaRII levels.
  • Smad2 and Smad4 nuclear translocation was similar in RIE-Ras and parental cells.
  • TIEG2 activity was reduced in RIE-Ras cells.

Conclusions:

  • TGFbeta resistance in Ras-transformed intestinal epithelial cells is associated with reduced TGFbetaRII expression.
  • The resistance mechanism involves transcriptional regulation, specifically affecting TIEG2 activity.
  • TGFbeta signaling pathway alterations contribute to gastrointestinal cancer development.

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