EPITHELIAL RAT-THYROID CELL CLONES, ESCAPING FROM TRANSFORMING GROWTH-FACTOR-BETA NEGATIVE GROWTH-CONTROL, ARE STILL INHIBITED BY THIS FACTOR IN THE ABILITY TO TRAP IODIDE

Transforming growth factor beta (TGF beta) acts on epithelial thyroid cells, negatively controlling their proliferation and functions. The e ffects of TGF beta on epithelial rat thyroid cells (FRTL-5) and on two TGF-beta-resistant rat thyroid cell clones (FRTL-5H2 and FRTL-R) were investigated. FRTL-5HZ. represents a rat thyroid cell clone overexpre ssing active erbB-2 oncogene, recently obtained after FRTL-5 cell infe ction with a retrovirus vector carrying the erbB-2 human oncogene (G. Mincione ef al., Cancer Res., 53: 5548-5553, 1993). FRTL-R is a FBTL-5 subclone spontaneously isolated after long term in culture. FRTL-5H2 and FRTL-R cell clones were stimulated by TGF beta at the same concent ration of 5 ng/ml that induced 70% inhibition of [H-3]thymidine incorp oration in control FRTL-5 thyroid cells. Nuclear events regulated by T GF beta, such as cyclin and cyclin-dependent kinase gene expression, w ere then analyzed. In FRTL-5 cells, TGF beta was found to reduce the e xpression of cdk2 and cyclin A genes; the same treatment did not modif y nuclear gene expression in the resistant cell clones. TGF beta is kn own to reduce iodide uptake in thyroid cells; in both FRTL-5H2 and FRT L-R cells, TGF beta was found to inhibit the thyrotropin-induced iodid e uptake. Thus, thyroid cell clones, resistant to the growth-inhibitor y activity of TGF beta, were sensitive to TGF beta inhibition of iodid e incorporation, suggesting that TGF beta activates divergent signalin g pathways in these cells, separately controlling cell proliferation a nd differentiation parameters. Studies on TGF beta receptors showed si milar amounts of TGF beta-binding species on FRTL-5 cells and TGF beta -resistant clones, while I-125-labeled TGF beta crosslinking experimen ts revealed differences; thus, the TGF beta-resistant cells showed a 4 0% decrease in the amount of labeled type II TGF beta receptor on the cell surface. However, this different pattern of TGF beta receptors ca nnot totally account for the shown TGF beta resistance to growth inhib ition that might also be due to perturbation in signaling pathways.