Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts
Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts
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DOI：
10.1128/mcb.01849-07
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发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Basilico, Claudio
中科院分区：
文献类型：
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作者：
Ambrosetti, Davide;Holmes, Greg;Basilico, Claudio
成纤维细胞生长因子（FGF）和Wnt信号对于适当的骨发育都是至关重要的。我们之前报道过，成骨细胞中激活性FGF受体突变的表达下调了许多被报道为Wnt信号传导靶点的基因的表达，这表明促进成骨细胞分化和功能的Wnt信号传导与抑制这些过程的FGF信号传导之间存在拮抗作用。为了分析FGF对成骨细胞中Wnt信号传导的影响，我们创建了报告细胞系，其中Wnt响应启动子驱动荧光素酶表达，并显示Wnt 3a诱导的荧光素酶表达被FGF处理特异性抑制。FGF特异性阻止Wnt诱导的TCF 1和-4与DNA上β-连环蛋白的转录复合物的形成。FGF没有显着影响P-连环蛋白的激活，虽然它减少了TCF/LEF因子的表达和Wnt对其的诱导。使用Wnt 3a和FGF单独或组合处理的成骨细胞的微阵列分析显示，约70%的由Wnt 3a诱导的基因通过组合FGF处理而下调。这些包括新的和以前确定的Wnt靶基因和基因参与成骨细胞分化。此外，FGF单独可下调四种Fzd Wnt受体基因的表达。我们的研究结果表明，FGF通过抑制Wnt诱导的转录来拮抗Wnt信号传导，并表明多种机制（包括TCF和Wnt受体的下调）促成了这种效应。
Fibroblast growth factor (FGF) and Wnt signals are both critical for proper bone development. We previously reported that the expression of activating FGF receptor mutations in osteoblasts downregulated the expression of many genes reported as targets of Wnt signaling, suggesting an antagonistic effect between Wnt signaling, which promotes osteoblast differentiation and function, and FGF signaling, which inhibits these processes. To analyze the effect of FGF on Wnt signaling in osteoblasts, we created reporter cell lines where a Wnt-responsive promoter drives luciferase expression and showed that Wnt3a-induced luciferase expression was specifically inhibited by FGF treatment. FGF specifically prevented the formation of a Wnt-induced transcriptional complex of TCF1 and -4 with beta-catenin on DNA. FGF did not significantly affect the activation of P-catenin, although it reduced both the expression of TCF/LEF factors and their induction by Wnt. Microarray analysis using osteoblasts treated with Wnt3a and FGF alone or in combination showed that about 70% of the genes induced by Wnt3a were downregulated by combined FGF treatment. These included novel and previously identified Wnt target genes and genes involved in osteoblast differentiation. Furthermore, FGF alone could downregulate the expression of four Fzd Wnt receptor genes. Our results show that FGF antagonizes Wnt signaling by inhibiting Wnt-induced transcription and suggest that multiple mechanisms, including downregulation of TCFs and Wnt receptors, contribute to this effect.