ROLE OF RECEPTOR COMPLEXES IN RESISTANCE OR SENSITIVITY TO GROWTH-INHIBITION BY TGF-BETA IN INTESTINAL EPITHELIAL-CELL CLONES

Untransformed rat intestinal epithelial cells (IEC-18) were chemically mutagenized, selected in the presence of TGFbeta1, and cloned by limiting dilution. Two clones (4-5, 4-6) were resistant to growth inhibition by both TGFbeta1 and TGFbeta2. Another clone (4-1) was more sensitive to both TGFbeta isoforms (relative to parental IEC-18 cells). IC50 values for TGFbeta1 and 2 in the 4-1 cells were at least 1/9 those of the parental cells; growth rates were reduced by 49% for TGFbeta1 and by 26% for TGFbeta2 in this clone. This increased sensitivity to TGFbeta was explained by the 5- to 10-fold increase, relative to parental cells, in binding of TGFbeta1 and TGFbeta2 to both the type I and II receptors. In contrast, the resistance to growth inhibition by TGFbeta in the 4-5 and 4-6 cells could not be explained by a decrease in either TGFbeta binding affinities or in total number of receptors expressed, by the presence of serum binding components, or by occupation of receptor binding sites with autocrine TGF-beta1. However, in comparison to TGFbeta-sensitive cells (IEC-18, 4-1), the resistant cells displayed a higher ratio of type II relative to type I receptor binding by TGF-beta1. Thus, a critical ratio of binding to receptor subtypes correlated with growth inhibition by TGF-beta1. Resistance to TGF-beta2 in the same clones did not appear to be receptor related. Thus, different mechanisms for resistance to TGF-beta1 and TGF-beta2 were observed within a given clone.