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Altered Responsiveness of Rat Liver Epithelial Cells to Transforming Growth Factor ß₁ following Their Transformation with v-raf

Laboratory of Experimental Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, NIH, Bethesda, Maryland 20892

The effects of transforming growth factor ß (type 1) (TGF-ß₁) on DNA synthesis, cell proliferation, and protein synthesis were examined in a series of v-raf-transformed rat liver epithelial (RLE) cells, which exhibit a range of transformed phenotypes. All of the transformed cells were relatively resistant to the growth-inhibitory effects of TGF-ß₁, compared to normal RLE cells and control cells infected with a helper virus. The more tumorigenic cell lines had very few surface receptors for TGF-ß₁ and showed no increase in the secretion of a number of specific proteins, including fibronectin, following TGF-ß₁ treatment. In contrast, the more normal-looking, less tumorigenic v-raf-transformed cells bound similar amounts of TGF-ß₁ as normal RLE and control cells and showed a similar pattern of TGF-ß₁-stimulated protein secretion. These findings suggest that the effects of TGF-ß₁ on cell proliferation and on the expression of certain secreted proteins are mediated through different mechanisms. Following transformation of RLE cells with v-raf, the signalling pathways controlling TGF-ß₁ growth inhibition are perturbed, while those involved in regulating the synthesis of certain proteins may remain intact. Thus, the escape from the various distinct biological effects of TGF-ß₁ may be an important stage in the progression of neoplastic transformation of RLE cells in vitro.

¹ Present address: Toxicology Department, Nestlé Research Centre, PO Box 44, Vers-Chez-Les-Blanc, CH-1000 Lausanne 26, Switzerland.

² To whom requests for reprints should be addressed, at Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 3C28, NIH, Bethesda, MD 20892.

Received 4/ 1/90. Accepted 8/31/90.

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