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c-Myc Is a Critical Target for C/EBPα in Granulopoiesis

机译：c-Myc是粒细胞生成中C /EBPα的关键靶标

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CCAAT/enhancer binding protein α (C/EBPα) is an integral factor in the granulocytic developmental pathway, as myeloblasts from C/EBPα-null mice exhibit an early block in differentiation. Since mice deficient for known C/EBPα target genes do not exhibit the same block in granulocyte maturation, we sought to identify additional C/EBPα target genes essential for myeloid cell development. To identify such genes, we used both representational difference analysis and oligonucleotide array analysis with RNA derived from a C/EBPα-inducible myeloid cell line. From each of these independent screens, we identified c-Myc as a C/EBPα negatively regulated gene. We mapped an E2F binding site in the c-Myc promoter as thecis-acting element critical for C/EBPα negative regulation. The identification of c-Myc as a C/EBPα target gene is intriguing, as it has been previously shown that down-regulation of c-Myc can induce myeloid differentiation. Here we show that stable expression of c-Myc from an exogenous promoter not responsive to C/EBPα-mediated down-regulation forces myeloblasts to remain in an undifferentiated state. Therefore, C/EBPα negative regulation of c-Myc is critical for allowing early myeloid precursors to enter a differentiation pathway. This is the first report to demonstrate that C/EBPα directly affects the level of c-Myc expression and, thus, the decision of myeloid blasts to enter into the granulocytic differentiation pathway.
机译：CCAAT /增强子结合蛋白α（C /EBPα）是颗粒细胞发育途径中不可或缺的因子，因为来自C /EBPα-null小鼠的成肌细胞显示出早期分化的障碍。由于缺乏已知C /EBPα靶基因的小鼠在粒细胞成熟中没有表现出相同的阻滞作用，因此我们寻求鉴定对髓样细胞发育必不可少的其他C /EBPα靶基因。为了鉴定此类基因，我们使用了代表性差异分析和寡核苷酸阵列分析，并使用了衍生自C /EBPα诱导的髓样细胞系的RNA。从这些独立的筛选中，我们确定c-Myc为C /EBPα负调控基因。我们将c-Myc启动子中的一个E2F结合位点定位为对C /EBPα负调控至关重要的顺式作用元件。将c-Myc鉴定为C /EBPα靶基因很有趣，因为先前已经证明c-Myc的下调可以诱导髓样分化。在这里，我们显示来自不响应C /EBPα介导的下调的外源启动子的c-Myc的稳定表达迫使成纤维细胞保持未分化状态。因此，c / Myc的C /EBPα负调控对于允许早期髓样前体进入分化途径至关重要。这是第一份证明C /EBPα直接影响c-Myc表达水平的报告，因此，也表明了髓母细胞进入粒细胞分化途径的决定。

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