Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling.

Bulus NM, Sheng HM, Sizemore N, Oldham SM, Barnett JV, Coffey RJ, Beauchamp DR, Barnard JA
Neoplasia. 2000 2 (4): 357-64

PMID: 11005570 · PMCID: PMC1550294

Ras-transformed intestinal epithelial cells are resistant to the growth inhibitory actions of TGFbeta and have a marked decrease in expression of the TGFbeta type II receptor (TGFbetaRII). Rat intestinal epithelial cells (RIE) were stably transfected with activated Ras, Sos and Raf constructs and tested for expression of TGFbetaRII and sensitivity to growth inhibition by TGFbeta. The parental RIE line and the RIE-Raf cells were non-transformed in morphology and were sensitive to TGFbeta (70-90% inhibited). In contrast, the RIE-Ras and RIE-Sos lines were transformed, resistant to TGFbeta and expressed 5- to 10-fold decreased levels of the TGFbetaRII mRNA and protein. Cyclin D1 protein expression was repressed by TGFbeta treatment in parental RIE and RIE-Raf cells, whereas levels of cyclin D1 in RIE-Ras and RIE-Sos cells remained unchanged. Treatment of RIE-Ras cells with 25 microM farnesyl transferase inhibitor, FTI L739,749, for 48 hours restored expression of TGFbetaRII to levels equivalent to control cells. In addition, treatment of RIE-Ras cells for 48 hours with PD-98059, a specific MAPKK inhibitor, also increased expression of TGFbetaRII to control levels. Collectively these results suggest that downregulation of TGFbetaRII and loss of sensitivity to growth inhibition by TGFbeta in Ras-transformed intestinal epithelial cells is not mediated exclusively by the conventional Ras/Raf/MAPKK/MAPK pathway. However, activation of MAPK, perhaps by an alternate Ras effector pathway, appears to be necessary for Ras-mediated downregulation of TGFbetaRII.

MeSH Terms (19)

Alkyl and Aryl Transferases Animals Cell Division Cell Line Cell Line, Transformed Enzyme Inhibitors Farnesyltranstransferase Flavonoids Gene Expression Regulation Genes, ras Intestinal Mucosa Oligopeptides Protein-Serine-Threonine Kinases Rats Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Signal Transduction Transfection Transforming Growth Factor beta

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