Fibroblast Growth Factor-2 Induces Lef/Tcf-dependent Transcription in Human Endothelial Cells

Abstract Lef/Tcf proteins belong to a family of architectural transcription factors that control developmental processes and play an important role in oncogenesis. Classical activators of Lef/Tcf-dependent transcription comprise the Wnt family of proteins, which translocate β-catenin into the nucleus and allow the formation of transactivation-competent Lef/Tcf-β-catenin complexes. Here we show that in human endothelial cells fibroblast growth factor-2 (FGF-2) reduces GSK-3 activity and augments nuclear levels of β-catenin. FGF-2 induced Lef/Tcf-dependent transcription of a cyclin D1-luciferase construct. Gel shift assays revealed binding of Tcf-4 as the only Lef/Tcf family member and of β-catenin to the Lef/Tcf site in the cyclin D1 promoter. Cotransfection with a dominant negative Tcf-4 construct inhibited the FGF-2-induced cyclin D1 promoter activity. Overexpression of an uninhibitable GSK-3β mutant resulted in partial inhibition of FGF-2-mediated cyclin D1 induction. The importance for cyclin D1 in FGF-2-induced angiogenesis in vivo is shown in cyclin D1−/− mice, where FGF-2-induced new vessel formation was significantly reduced compared with FGF-2-induced angiogenesis in cyclin D1+/+ mice. In conclusion, FGF-2 is a novel modulator of Lef/Tcf-β-catenin signaling in endothelial cells, suggesting that angiogenic properties of FGF-2 are at least in part mediated by Lef/Tcf-β-catenin activation.