Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein ε
Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein ε
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DOI：
10.1182/blood.v98.4.897
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发表时间：
2001-08-15
期刊：
影响因子：
20.3
通讯作者：
Ihle, JN
中科院分区：
文献类型：
--
作者：
Nakajima, H;Ihle, JN
粒细胞集落刺激因子(G-CSF)是调节髓系细胞增殖和分化的主要细胞因子，但G-CSF控制髓系分化的机制尚不清楚。造血细胞的分化受谱系特异性转录因子的调控，基因靶向研究表明CCAAT/增强子结合蛋白(C/EBP)α和C/EBP epsilon分别在粒细胞分化的早期和中晚期起关键作用。这种表达的信号需要包含G-CSF受体的第一个酪氨酸残基的区域。显性-负性信号转导和转录激活子3可阻断G-CSF诱导的32D细胞的粒细胞分化，但不能阻断C/EBP epsilon的诱导，表明这些蛋白在不同的途径中发挥作用。研究还发现，C/EBP epsilon的过度表达极大地促进了G-CSF对粒细胞的分化，令人惊讶的是，仅C/EBP epsilon的表达就足以使细胞分化为形态和功能成熟的粒细胞。C-myc的过表达抑制了造血细胞的分化，但其分子机制尚不完全清楚。在高表达c-myc而不能通过G-CSF进行分化的32Dcl3细胞中，C/EBP epsilon的诱导完全被取消。在这些细胞中异位表达C/EBP epsilon诱导分化特征，包括核形态特征的改变和颗粒的出现。这些数据表明，C/EBP epsilon是G-CSF调节的粒细胞分化的限速步骤，c-myc拮抗G-CSF诱导的髓系分化，至少部分是通过抑制C/EBP epsilon的诱导。(C)2001年，由美国血液病学会提供。
Granulocyte colony-stimulating factor (G-CSF) is a major cytokine that regulates proliferation and differentiation of myeloid cells, although the underlying mechanisms by which G-CSF controls myeloid differentiation are largely unknown. Differentiation of hematopoietic cells is regulated by lineage-specific transcription factors, and gene-targeting studies previously revealed the critical roles of CCAAT/enhancer-binding protein (C/EBP) alpha and C/EBP epsilon, respectively, in the early and mid-late stages of granulocyte differentiation, The expression of C/EBP epsilon in 32Dcl3 cells and FDCP1 cells expressing mutant G-CSF receptors was examined and it was found that G-CSF up-regulates C/EBP epsilon. The signal for this expression required the region containing the first tyrosine residue of G-CSF receptor. Dominant-negative signal transducers and activators of transcription 3 blocked G-CSF-induced granulocytic differentiation in 32D cells but did not block induction of C/EBP epsilon, indicating that these proteins work in different pathways. It was also found that overexpression of C/EBP epsilon greatly facilitated granulocytic differentiation by G-CSF and, surprisingly, that expression of C/EBP epsilon alone was sufficient to make cells differentiate into morphologically and functionally mature granulocytes. Overexpression of c-myc inhibits differentiation of hematopoietic cells, but the molecular mechanisms of this inhibition are not fully understood. In 32Dcl3 cells overexpressing c-myc that do not differentiate by means of G-CSF, induction of C/EBP epsilon is completely abrogated. Ectopic expression of C/EBP epsilon in these cells induced features of differentiation, including changes in nuclear morphologic characteristics and the appearance of granules. These data show that C/EBP epsilon constitutes a rate-limiting step in G-CSF-regulated granulocyte differentiation and that c-myc antagonizes G-CSF-induced myeloid differentiation, at least partly by suppressing induction of C/EBP epsilon. (C) 2001 by The American Society of Hematology.