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Transforming Growth Factor-ß1 Induces Transforming Growth Factor- Promoter Activity and Transforming Growth Factor- Secretion in the Human Colon Adenocarcinoma Cell Line FET¹

Bristol-Myers Squibb, Princeton, New Jersey 08540, and Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699 [M. G. B.]

FET cells are well differentiated human adenocarcinoma cells whose growth is partially inhibited (50–60%) by transforming growth factor-ß1 (TGF-ß1). In exponentially growing cultures, TGF-ß1 induces the expression of transforming growth factor- (TGF-) by 3-fold. To determine whether this induction is the result of increased TGF- promoter activity, FET cells were transiently transfected with a plasmid containing 2816 base pairs of the 5'-flanking region of the TGF- gene linked to luciferase. Transfected FET cells treated with growth-inhibitory concentrations of TGF-ß1 (10 ng/ml) showed up to a 10-fold increase in luciferase activity. The increase in luciferase activity was dose dependent through the normal physiological range of TGF-ß1 (0.5–20 ng/ml), saturating at 10 ng/ml. This effect was also TGF- promoter specific, inasmuch as the Rous sarcoma virus long terminal repeat used as a control remained relatively insensitive to the effects of TGF-ß1. By using progressively smaller portions of the TGF- promoter region, the TGF-ß1-responsive element was mapped between base pairs -77 and -201 of the 5'-flanking region. TGF-ß1 treatment also affected epidermal growth factor receptor levels. FET cells treated with TGF-ß1 (10 ng/ml) for 48 h showed a 20% decrease in the number of epidermal growth factor receptors and a 2-fold increase in the number of high affinity epidermal growth factor receptors on their surface. These results indicate that TGF-ß1 acts as a positive regulator of TGF- transcription, and they suggest a possible mechanism by which these cells circumvent the growth-inhibitory effects of TGF-ß1.

¹ This work was supported in part by National Cancer Institute Grants CA34432, CA45967, and CA50457.

² To whom requests for reprints should be addressed, at Department of Molecular Drug Mechanism, K2809, Bristol-Myers Squibb, Route 206 and Provinceline Road, Princeton, NJ 08540.

Received 8/ 6/92. Accepted 6/28/93.

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