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Restored expression of transforming growth factor beta type II receptor in k-ras-transformed thyroid cells, TGF
A Coppa1, G Mincione, D Lazzereschi
1Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Roma, Italy.
Abstract:
Transforming growth factor beta 1 (TGF beta 1) inhibits the growth of normal rat epithelial thyroid cells (FRTL-5 strain) by counteracting thyrotropin (TSH)-stimulated DNA synthesis and by slowing the cells in the G1 phase of the cell cycle. Here, we have studied two clones of FRTL-5 thyroid cell line transformed by the wild type (wt) v-k-ras oncogene (K.M.A1, K.M.A2) and one clone (A6) transformed by a temperature-sensitive (ts) v-k-ras mutant. Anchorage-dependent as well as anchorage-independent growth of these k-ras-transformed cells was not inhibited by TGF beta 1. TGF beta 1 resistance appeared to be dependent by a functional p21 k-ras, because A6 cell growth was partially inhibited at the nonpermissive temperature (39 degrees C). To determine the basis for TGF beta 1 resistance in k-ras-transformed thyroid cells, we looked for possible defects in the expression of type I (T beta R-I/ALK5) and type II TGF beta receptors (T beta R-II). Lower levels of type II receptors were present in all of the k-ras-transformed clones, as revealed by both Northern blot and cross-linking experiments. A partial reversion of the malignant phenotype of the wt k-ras-transformed clone was obtained in two clones isolated after transfection of the malignant thyroid cells (K.M.A1) with a T beta R-II expression vector. These two clones also showed restored levels of exogenous T beta R-II mRNA and protein, and both clones showed a partially reacquired sensitivity to TGF beta 1. Similarly, the reversion of the malignant phenotype of the A6 clone grown at the nonpermissive temperature was accompanied by a restored expression of the T beta R-II receptors. These data indicate that active k-ras oncogene can induce TGF beta 1 resistance in rat thyroid cells and suggest that one of the possible mechanisms of escape from TGF beta 1 growth control in k-ras-induced thyroid carcinogenesis involves a reduced expression of T beta R-II receptors.