C-Myc is a critical target for C/EBPα in granulopoiesis
C-Myc is a critical target for C/EBPα in granulopoiesis
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DOI：
10.1128/mcb.21.11.3789-3806.2001
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发表时间：
2001-06-01
影响因子：
5.3
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
Johansen, LM;Iwama, A;Tenen, DG
CCAAT/增强子结合蛋白α (C/EBP α)是粒细胞发育途径中不可或缺的因素，因为来自C/EBP α -缺失小鼠的成髓细胞在分化过程中表现出早期阻滞。由于缺乏已知C/EBP α靶基因的小鼠在粒细胞成熟过程中不会表现出相同的阻滞，因此我们试图确定对髓细胞发育至关重要的其他C/EBP α靶基因。为了鉴定这些基因，我们对来自C/EBP α诱导的骨髓细胞系的RNA进行了代表性差异分析和寡核苷酸阵列分析。从这些独立筛选中，我们确定C - myc为C/EBP α负调控基因。我们将C - myc启动子中的E2F结合位点定位为C/EBP α负调控的关键顺式作用元件。C - myc作为C/EBP α靶基因的鉴定是有趣的，因为之前已经表明下调C - myc可以诱导髓细胞分化。在这里，我们发现来自外源性启动子的C - myc的稳定表达对C/EBP α介导的下调没有反应，迫使成髓细胞保持未分化状态。因此，C/EBP α负调控C - myc对于允许早期髓细胞前体进入分化途径至关重要。这是第一个证明C/EBP α直接影响C - myc表达水平，从而影响髓母细胞进入粒细胞分化途径的决定的报告。
CCAAT/enhancer binding protein alpha (C/EBP alpha) is an integral factor in the granulocytic developmental pathway, as myeloblasts from C/EBP alpha -null mice exhibit an early block in differentiation. Since mice deficient for known C/EBP alpha target genes do not exhibit the same block in granulocyte maturation, we sought to identify additional C/EBP alpha 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/EBP alpha -inducible myeloid cell line. From each of these independent screens, we identified c-Myc as a C/EBP alpha negatively regulated gene. We mapped an E2F binding site in the c-Myc promoter as the cis-acting element critical for C/EBP alpha negative regulation. The identification of c-Myc as a C/EBP alpha 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/EBP alpha -mediated down-regulation forces myeloblasts to remain in an undifferentiated state. Therefore, C/EBP alpha 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/EBP alpha directly affects the level of c-Myc expression and, thus, the decision of myeloid blasts to enter into the granulocytic differentiation pathway.