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Control of the Expression of c-sis mRNA in Human Glioblastoma Cells by Phorbol Ester and Transforming Growth Factor ß¹

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106

The regulation of c-sis oncogene expression in human glioblastoma cell line A172 has been investigated using a sensitive RNA-RNA solution hybridization method. Enhanced expression of c-sis mRNA was induced by phorbol ester (PMA) and diacylglycerol, each of which activates protein kinase C. c-sis mRNA was also induced by transforming growth factor ß (TGF-ß). The response to PMA and TGF-ß was transient, and in each case the decrease in c-sis mRNA level following maximum stimulation occurred with a half-life similar to the mRNA half-life previously determined. Cycloheximide had no significant effect on the induction of c-sis mRNA by either PMA or TGF-ß. The increases in c-sis mRNA following addition of either PMA or TGF-ß correlated well with increases in c-sis transcription as observed by the nuclear run-on technique. In cells in which protein kinase C had been down-regulated, there was no inhibition of the c-sis mRNA response to TGF-ß. Furthermore in cells pretreated with TGF-ß, induction by PMA was unaffected. Thus the TGF-ß signal pathway does not involve activation of protein kinase C, and at least two initially distinct intracellular signaling routes lead to activation of c-sis gene expression in this glioblastoma cell line. The protein kinase inhibitor H7 abolished the ability of not only PMA but also of TGF-ß to induce c-sis mRNA. The ability of H7 to inhibit the TGF-ß stimulation suggests that a protein kinase other than protein kinase C is involved in the signal transduction by TGF-ß.

¹ Supported by Grants NIH 5-R01-42121, NIH 5-K06-GM 21444, NIH P30 CA 43703, and DOE-DE-FG02-87ER60587.

² To whom requests for reprints should be addressed.

Received 6/13/88. Revised 11/17/88. Revised 3/ 1/89. Accepted 3/ 7/89.