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Inhibitory Effects of Transforming Growth Factor ß₁ on Mitogenic Response, Transforming Growth Factor , and c-myc in Quiescent, Well-Differentiated Colon Carcinoma Cells¹

Department of Pharmacology, Baylor College of Medicine [K. M. M., Q. Z., H. G. C.], and Bristol-Baylor Labs, Baylor College of Medicine [L. E. H., M. G. B.] Houston, Texas 77030

Previously, we reported that exponentially proliferating cultures of well-differentiated human colon carcinoma cells responded to transforming growth factor ß₁ (TGF-ß) with growth inhibition, alterations in morphology, and increased secretion of the differentiation marker, carcinoembryonic antigen. Poorly differentiated cultures were unresponsive. Here we show that TGF-ß was ineffective in repressing nutrient-stimulated mitogenesis in quiescent, poorly differentiated cells. However, in quiescent, well-differentiated cells, TGF-ß repressed the mitogenic responses to both nutrients alone (by 90%) and to nutrients plus the exogenous stimulatory factors epidermal growth factor (E), insulin (I), and transferrin (T) (by 55–65%). Thymidine incorporation experiments indicated that TGF-ß reduced both the onset and peak mitogenic response to growth factors and/or nutrients in the well-differentiated cells. Additionally, TGF-ß repressed the growth factor (E + I + T)-stimulated up-regulation of expression of both c-myc and of transforming growth factor (TGF-) mRNAs in quiescent, well-differentiated cells. TGF-ß also elicited a rapid (t 1h) down-regulation of c-myc expression in the absence of prior growth factor (E + I + T) stimulation. In contrast, TGF-ß had no effect on c-myc or TGF- mRNA expression in the poorly differentiated cells. The results suggest that TGF-ß exerts rapid inhibitory effects on proliferation-associated genes in quiescent and restimulated, well-differentiated cells. Expression of these genes (c-myc and TGF-) may otherwise (in the absence of TGF-ß) play roles in the cellular signaling of mitogenic responses by growth stimulatory factors in well-differentiated colon carcinoma cells.

¹ Supported by NIH Grants CA51452 to K. M. M. and CA50457 to M. G. B. from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Dept. of Pharmacology, Baylor College of Medicine, Houston, TX 77030.

Received 3/15/90. Accepted 8/30/90.

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