Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Exp Cell Res. 2010 Jan 15;316(2):194-202. doi: 10.1016/j.yexcr.2009.08.008. Epub 2009 Aug 21.
Skeletal muscle development is partly characterized by myoblast proliferation and subsequent differentiation into postmitotic muscle fibers. Developmental regulation of expression of the fibroblast growth factor receptor 1 (FGFR1) gene is required for normal myoblast proliferation and muscle formation. As a result, FGFR1 promoter activity is controlled by multiple transcriptional regulatory proteins during both proliferation and differentiation of myogenic cells. The transcription factor AP-2 alpha is present in nuclei of skeletal muscle cells and suppresses myoblast proliferation in vitro. Since FGFR1 gene expression is tightly linked to myoblast proliferation versus differentiation, the FGFR1 promoter was examined for candidate AP-2 alpha binding sites. Mutagenesis studies indicated that a candidate binding site located at -1035 bp functioned as a repressor cis-regulatory element. Furthermore, mutation of this site alleviated AP-2 alpha-mediated repression of FGFR1 promoter activity. Chromatin immunoprecipitation studies demonstrated that AP-2 alpha interacted with the FGFR1 promoter in both proliferating myoblasts and differentiated myotubes. In total, these results indicate that AP-2 alpha is a transcriptional repressor of FGFR1 gene expression during skeletal myogenesis.
骨骼肌的发育部分特征在于成肌细胞的增殖，随后分化为有丝分裂后肌肉纤维。成纤维细胞生长因子受体 1（FGFR1）基因的发育调控对于正常的成肌细胞增殖和肌肉形成是必需的。因此，FGFR1 启动子活性在成肌细胞的增殖和分化过程中受到多种转录调节蛋白的控制。转录因子 AP-2 alpha 存在于骨骼肌细胞的核内，并在体外抑制成肌细胞的增殖。由于 FGFR1 基因表达与成肌细胞的增殖与分化密切相关，因此对 FGFR1 启动子进行了候选 AP-2 alpha 结合位点的检测。突变研究表明，位于-1035bp 的候选结合位点作为一个抑制性顺式调控元件起作用。此外，该位点的突变减轻了 AP-2 alpha 对 FGFR1 启动子活性的抑制作用。染色质免疫沉淀研究表明，AP-2 alpha 在增殖的成肌细胞和分化的肌管中均与 FGFR1 启动子相互作用。总的来说，这些结果表明，AP-2 alpha 是骨骼肌发生过程中 FGFR1 基因表达的转录抑制因子。
