The Small GTPases Ras, Rac, and Cdc42 Transcriptionally Regulate Expression of Human Fibroblast Growth Factor 1

Abstract

Four distinct promoters (1A, 1B, 1C, and 1D) of fibroblast growth factor 1 (FGF1), spaced up to 70 kilobase pairs apart, direct the expression of alternatively spliced transcript variants (FGF1.A, -1. B, -1.C, and -1.D) that encode FGF1. These FGF1 transcripts can be detected in cultured cells as well as in normal and diseased tissues. These transcripts are differentially regulated in a cell-specific manner. To further delineate the biological function of multiple promoter usage by a single gene, we investigated the transcriptional regulation of these promoters by defined signaling pathways associated with cell proliferation and cell survival. Here we show a specific association of two of the FGF1 promoters, 1C and 1D, with signaling cascades of the Ras superfamily of GTPases. A serum-response element, comprised of the Ets and CArG motifs, present in promoter 1D was shown to be the target of distinct signaling cascades; the Ets motif target of Ras, Rac1, and Cdc42 regulation; and the CArG motif target of de novo protein synthesis-independent cascade. Ras and Rac1 also activated the FGF2 promoter. Further, the transcription factor Ets2 synergistically activated FGF1 gene, but not FGF2, in a Ras- and Rac1-dependent signaling pathway. In support of these conclusions high levels of intracellular FGF1 were detected in cells undergoing cytokinesis. Altogether, our results suggest that FGF1 may play a fundamental role in cell division, spreading, and migration, in addition to cell proliferation.