Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada.
Cell Death Dis. 2013 Jun 27;4(6):e692. doi: 10.1038/cddis.2013.221.
Activator protein-1 (AP-1) is a ubiquitous transcription factor that paradoxically also has some tissue-specific functions. In skeletal muscle cells, we document that the AP-1 subunit, Fra-2, is expressed in the resident stem cells (Pax7-positive satellite cells) and also in the analogous undifferentiated 'reserve' cell population in myogenic cultures, but not in differentiated myofiber nuclei. Silencing of Fra-2 expression enhances the expression of differentiation markers such as muscle creatine kinase and myosin heavy chain, indicating a possible role of Fra-2 in undifferentiated myogenic progenitor cells. We observed that Fra-2 is a target of cytokine-mediated extracellular signal-regulated kinase-1/2 signaling in cultured muscle cells, and extensive mass spectrometry and mutational analysis identified S320 and T322 as regulators of Fra-2 protein stability. Interestingly, Fra-2 S320 phosphorylation occurs transiently in activated satellite cells and is extinguished in myogenin-positive differentiating cells. Thus, cytokine-mediated Fra-2 expression and stabilization is linked to regulation of myogenic progenitor cells having implications for the molecular regulation of adult muscle stem cells and skeletal muscle regeneration.
激活蛋白-1 (AP-1) 是一种普遍存在的转录因子，但它也具有一些组织特异性功能。在骨骼肌细胞中，我们证明了 AP-1 亚基 Fra-2 不仅在常驻干细胞（Pax7 阳性卫星细胞）中表达，而且在成肌培养物中的类似未分化“储备”细胞群体中表达，但不在分化的肌纤维核中表达。Fra-2 表达的沉默增强了分化标志物的表达，如肌酸激酶和肌球蛋白重链，表明 Fra-2 可能在未分化的成肌祖细胞中发挥作用。我们观察到 Fra-2 是细胞因子介导的细胞外信号调节激酶-1/2 信号在培养的肌肉细胞中的靶标，广泛的质谱分析和突变分析确定 S320 和 T322 是 Fra-2 蛋白稳定性的调节剂。有趣的是，Fra-2 的 S320 磷酸化在激活的卫星细胞中短暂发生，并在肌球蛋白阳性分化细胞中消失。因此，细胞因子介导的 Fra-2 表达和稳定与成肌祖细胞的调节有关，这对成年肌肉干细胞和骨骼肌再生的分子调节具有重要意义。
