Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells.
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 beta-catenin into the nucleus and allow the formation of transactivation-competent Lef/Tcf-beta-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 beta-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 beta-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-3beta 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-beta-catenin signaling in endothelial cells, suggesting that angiogenic properties of FGF-2 are at least in part mediated by Lef/Tcf-beta-catenin activation.
Holnthoner
Wolfgang
W
Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Pillinger
Manuela
M
Groger
Marion
M
Wolff
Klaus
K
Ashton
Anthony W
AW
Albanese
Chris
C
Neumeister
Peter
P
Pestell
Richard G
RG
Petzelbauer
Peter
P
D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D016222:Fibroblast Growth Factor 2; D019938:Cyclin D1; D038362:Glycogen Synthase Kinase 3