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Updated: Jun 27, 2026
10:21
Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling
N M Bulus1, H M Sheng, N Sizemore
1Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Neoplasia (New York, N.Y.)
|September 27, 2000
Summary
Ras transformation in intestinal cells reduces TGF-beta type II receptor (TGFbetaRII) expression, causing growth resistance. Farnesyl transferase or MAPKK inhibition restored TGFbetaRII levels, suggesting alternative pathways are involved.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Ras-transformed cells often exhibit resistance to growth inhibitory signals like TGFbeta.
- Decreased expression of the TGFbeta type II receptor (TGFbetaRII) is observed in Ras-transformed intestinal epithelial cells.
- Understanding the mechanisms behind this resistance is crucial for cancer therapy.
Purpose of the Study:
- To investigate the role of Ras, Sos, and Raf in TGFbetaRII expression and TGFbeta sensitivity in rat intestinal epithelial cells (RIE).
- To determine if the conventional Ras/Raf/MAPKK/MAPK pathway mediates the downregulation of TGFbetaRII in Ras-transformed cells.
- To explore potential therapeutic interventions targeting Ras-mediated resistance.
Main Methods:
- Stable transfection of RIE cells with activated Ras, Sos, and Raf constructs.
- Analysis of TGFbetaRII mRNA and protein expression levels.
- Assessment of sensitivity to TGFbeta-induced growth inhibition.
- Treatment with farnesyl transferase inhibitor (FTI L739,749) and MAPKK inhibitor (PD-98059).
Main Results:
- Ras and Sos transformed RIE cells showed decreased TGFbetaRII expression (5-10 fold) and resistance to TGFbeta.
- Parental RIE and RIE-Raf cells remained sensitive to TGFbeta and maintained normal TGFbetaRII levels.
- TGFbeta treatment repressed cyclin D1 in parental and RIE-Raf cells, but not in RIE-Ras and RIE-Sos cells.
- FTI L739,749 and PD-98059 treatments restored TGFbetaRII expression in RIE-Ras cells.
Conclusions:
- Downregulation of TGFbetaRII and loss of TGFbeta sensitivity in Ras-transformed intestinal cells is not solely mediated by the canonical Ras/Raf/MAPKK/MAPK pathway.
- Activation of MAPK, potentially through alternative Ras effector pathways, is necessary for Ras-induced TGFbetaRII downregulation.
- Targeting alternative Ras effector pathways or downstream signaling may overcome TGFbeta resistance in intestinal cancers.
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