FGF-1-INDUCED PLATELET-DERIVED GROWTH FACTOR-A CHAIN GENE-EXPRESSION IN ENDOTHELIAL-CELLS INVOLVES TRANSCRIPTIONAL ACTIVATION BY EARLY GROWTH-RESPONSE FACTOR-I

Fibroblast growth factor-1 (FGF-1), a prototype member of the heparin- binding growth factor family, is a potent mitogen for vascular endothe lial cells and a variety of other cell types. FGF-1 can induce the exp ression of the platelet-derived growth factor-A chain (PDGF-A) gene in endothelial cells; however, the underlying transcriptional mechanisms are not known. We used serial 5' deletion and transient transfection analysis of the human PDGF-A promoter to demonstrate that a 16-bp elem ent, located 55 to 71 bp upstream of the transcriptional start site, i s required for FGF-1-inducible promoter-dependent expression. This reg ion contains nucleotide recognition elements for the early growth resp onse gene product, early growth response factor-1 (Egr-1), and the rel ated zinc-finger transcription factor, Spl. Reverse-transcription poly merase chain reaction revealed that FGF-1 induced Egr-1 mRNA expressio n within 30 minutes. Electrophontic mobility shift, supershift, and We stern blot analysis demonstrated that Egr-1 protein accumulated in the nuclei of endothelial cells exposed to the growth factor, whereas lev els of Spl did not change. Egr-1 bound to the FGF-I response element i n the proximal PDGF-A promoter in a specific and time-dependent manner . These findings indicate that Egr-1 plays a key regulatory role in FG F-l-inducible endothelial PDGF-A expression and implicate this transcr iption factor in pathological settings in which these mitogens are bot h expressed.