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Restored expression of transforming growth factor β type II receptor in k‐ras ‐transformed thyroid cells, TGFβ‐resistant, reverts their malignant phenotype
Author(s) -
Coppa Anna,
Mincione Gabriella,
Lazzereschi Davide,
Ranieri Annalisa,
Turco Alessandra,
Lucignano Barbara,
Scarpa Susanna,
RaganoCaracciolo Maria,
Colletta Giulia
Publication year - 1997
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199708)172:2<200::aid-jcp7>3.0.co;2-s
Subject(s) - transforming growth factor , phenotype , cancer research , receptor , thyroid , biology , endocrinology , microbiology and biotechnology , medicine , gene , genetics
Transforming growth factor β1 (TGFβ1) 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 TGFβ1. TGFβ1 resistance appeared to be dependent by a functional p21 k‐ras , because A6 cell growth was partially inhibited at the nonpermissive temperature (39°C). To determine the basis for TGFβ1 resistance in k‐ras ‐transformed thyroid cells, we looked for possible defects in the expression of type I (TβR‐I/ALK5) and type II TGFβ receptors (TβR‐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 TβR‐II expression vector. These two clones also showed restored levels of exogenous TβR‐II mRNA and protein, and both clones showed a partially reacquired sensitivity to TGFβ1. Similarly, the reversion of the malignant phenotype of the A6 clone grown at the nonpermissive temperature was accompanied by a restored expression of the TβR‐II receptors. These data indicate that active k‐ras oncogene can induce TGFβ1 resistance in rat thyroid cells and suggest that one of the possible mechanisms of escape from TGFβ1 growth control in k‐ras ‐induced thyroid carcinogenesis involves a reduced expression of TβR‐II receptors. J. Cell. Physiol. 172:200–208, 1997. © 1997 Wiley‐Liss, Inc.