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Regulation of Multiple Basic Fibroblast Growth Factor Messenger Ribonucleic Acid Transcripts by Protein Kinase C Activators

Department of Physiology, Faculty of Medicine, University of Manitoba Winnipeg, Manitoba, Canada R3E 0W3

Address requests for reprints to: Dr. Paul R. Murphy, Department of Physiology, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W3.

Abstract

The human astrocytoma cell line U87-MG expressed two major basic fibroblast growth factor (FGF) mRNA transcripts of 7.0 and 3.7 kilobase (kb), as well as several low abundance transcripts of lower mol wt (1.0–1.8 kb). The phorbol ester phorbol-12,13-dibutyrate caused a time- and dose-dependent increase in the abundance of basic FGF mRNA transcripts. At a concentration of 1 µM, phorbol ester increased the level of both the 7.0 and 3.7 kb transcripts within 4 h, reached a plateau at 1.5- to 2.5-fold above control levels by 6 h and remained elevated for at least 12 h. When measured at 6 h after drug addition, the abundance of both 7.0 and 3.7 kb transcripts was maximally stimulated by 100 nM phorbol ester (EC₅₀ = 10–20 nM). FGF mRNA levels were also stimulated to a similar extent by platelet-derived growth factor (0.15–5 U/ml) or the synthetic diacycglycerol analog 1-oleoyl-2-acetyl-rac glycerol (1–300 nM) at doses which stimulated DNA synthesis in these cells. Neither (Bu)₂cAMP (0.03–2 mM) nor A23187 (0.3–1000 nM) had any effect on FGF expression.

When U87-MG cells were exposed to phorbol ester for 24 h several differences were observed: the dose response curve was shifted to the left (EC₅₀ = 3–5 nM; maximum response at 10 nM phorbol ester) and the response of the 7.0 and 3.7 kb transcripts was attenuated at higher doses (100–1000 nM), perhaps reflecting down-regulation of protein kinase C by the phorbol ester. In addition, prolonged exposure to phorbol ester stimulated (2.8- to 3-fold) the expression of two low mol wt transcripts of approximately 1.5 and 1.8 kb in size. These data demonstrate that FGF mRNA expression is regulated by protein kinase C and provide evidence that multiple FGF mRNAs (perhaps resulting from alternative splicing) are capable of being transcribed under different conditions.

FOOTNOTES

This work was supported by grants from the MRC and National Cancer Institutes of Canada.

Received for publication July 11, 1988. Accepted for publication August 16, 1988.

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