The amino terminal and E2F interaction domains are critical for C/EBPα-mediated induction of granulopoietic development of hematopoietic cells
The amino terminal and E2F interaction domains are critical for C/EBPα-mediated induction of granulopoietic development of hematopoietic cells
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DOI：
10.1182/blood-2003-02-0479
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发表时间：
2003-11-01
期刊：
影响因子：
20.3
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
D'Alo, F;Johansen, LM;Tenen, DG
转录因子C/EBPalpha（CCAAT/增强子结合蛋白a）对粒细胞生成至关重要。小鼠中的基因破坏阻断了早期粒细胞分化，并且C/EBPalpha功能的破坏与人类急性髓性白血病（AML）有关，但是还没有进行系统的结构-功能分析来确定涉及C/EBPalpha介导的粒细胞分化的机制。在这里，我们证明了2个关键区域中的任何一个的丢失都会导致C/EBPalpha粒细胞发育的破坏：氨基末端和位于碱性区域的非DNA结合面上的特定残基。任一突变导致E2 F的C/EBPalpha抑制的丧失和c-Myc的下调，但只有碱性区的突变导致与E2 F的物理相互作用的丧失。相反，虽然氨基末端突变体保留了与E2 F相互作用的能力，但该突变体不能有效地结合C/EBPalpha位点，不能激活C/EBPalpha靶基因，并且在抑制E2 F活性方面也有缺陷。这些结果进一步强调了抑制粒细胞生成中增殖途径的重要性，并证明了C/EBPalpha蛋白的几个区域参与了这一机制。(C)2003年，美国血液学会。
The transcription factor C/EBPalpha (CCAAT/enhancer binding protein a) is critical for granulopoiesis. Gene disruption in mice blocks early granulocyte differentiation and disruption of C/EBPalpha function has been implicated in human acute myeloid leukemia (AML), but no systematic structure-function analysis has been undertaken to identify the mechanisms involved in C/EBPalpha-mediated granulocyte differentiation. Here we demonstrate that loss of either of 2 key regions results in disruption of C/EBPalpha granulocytic development: the amino terminus and specific residues residing on the non-DNA binding face of the basic region. Mutation of either results in loss of C/EBPalpha inhibition of E2F and down-regulation of c-Myc, but only mutation of the basic region results in loss of physical interaction with E2F. In contrast, while the amino terminal mutant retains the ability to interact with E2F, this mutant fails to bind a C/EBPalpha site efficiently, fails to activate C/EBPalpha target genes, and is also defective in inhibition of E2F activity. These results further emphasize the importance of inhibition of proliferative pathways in granulopoiesis and demonstrate that several regions of the C/EBPalpha protein are involved in this mechanism. (C) 2003 by The American Society of Hematology.