Repression of fibroblast growth factor receptor 1 gene expression by E2F4 in skeletal muscle cells.

Fibroblast growth factor receptor 1 (FGFR1) gene expression is positively and negatively regulated during muscle differentiation. We recently reported that FGFR1 gene expression was up-regulated by Sp transcription factors in proliferating myoblasts. However, the mechanism of down-regulation of this gene during differentiation is unknown. We have identified the transcription factor E2F4 as a negative regulator of FGFR1 gene expression. Immunodetection studies revealed that endogenous E2F1 and E2F2 proteins were cytoplasmic in myoblasts and myotubes, whereas E2F4 was abundant in the nuclei of both. Upon overexpression, E2F4 repressed FGFR1 promoter activity in a dose-dependent manner in myoblasts and Drosophila SL2 cells, and mutation of the E2F4 binding site increased FGFR1 promoter activity and reduced E2F4-mediated repression. Gel shift assays detected E2F4 binding to a synthetic FGFR1 E2F4 binding site and chromatin immunoprecipitation assays detected E2F4 binding to the endogenous FGFR1 promoter in proliferating myoblasts and myotubes. The results indicate that FGFR1 promoter activity in skeletal muscle cells is repressed by E2F4.