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Suppression of Synthesis and Utilization of Tropomyosin in Mouse and Rat Fibroblasts by Transforming Growth Factor : A Pathway in Oncogene Action

Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland 20892

Two events which commonly occur during transformation of murine and avian fibroblasts by retroviral oncogenes are production of transforming growth factor (TGF-) and suppression of tropomyosin synthesis. TGF has been proposed as a mediator of transformation through autocrine stimulation. Suppression of tropomyosin synthesis may contribute to the transformed phenotype through destabilization of actin microfilaments and cytoskeletal derangement. To determine whether suppression of tropomyosin synthesis might be a consequence of the action of TGF- we studied tropomyosin synthesis in rat (normal rat kidney) and mouse (NIH3T3) fibroblasts treated with TGF-. In a serum-containing system, addition of TGF- or epidermal growth factor to normal rat kidney monolayers in subnanomolar concentrations induced morphological changes consistent with transformation. These changes were accompanied by prominent suppression of synthesis of M_r 36,000 and 39,000 tropomyosins. Similar suppression was observed in NIH3T3 cells. Inhibition of tropomyosin synthesis began almost immediately after addition of TGF- and became progressively more pronounced during the succeeding 48 h. Suppression of tropomyosin synthesis was correlated with reduced expression of 1.1- and 1.8-kilobase tropomyosin mRNAs in both TGF-treated normal rat kidney cells and v-Ki-ras-transformed NIH3T3 cells. Rapid onset of a specific block in utilization of newly synthesized tropomyosin for formation of cytoskeletal elements was also demonstrated following TGF- treatment. The evidence suggests that this block may be a specific effect of TGF- treatment and that reduced expression of tropomyosin gene products may be either an independent event or a regulatory consequence of the block to utilization. The data support the conclusion that suppression of tropomyosin synthesis in cells transformed by a number of retroviral oncogenes results from the autocrine action of TGF-.

¹ To whom requests for reprints should be addressed.

Received 1/21/87. Revised 5/ 5/87. Accepted 5/11/87.

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