Defective gene expression, S phase progression, and maturation during hematopoiesis in E2F1/E2F2 mutant mice
Defective gene expression, S phase progression, and maturation during hematopoiesis in E2F1/E2F2 mutant mice
复制标题
DOI：
10.1128/mcb.23.10.3607-3622.2003
复制
发表时间：
2003-05-01
影响因子：
5.3
通讯作者：
DeGregori, J
中科院分区：
文献类型：
--
作者：
Li, FX;Zhu, JW;DeGregori, J
EN通过调节参与核苷酸合成、DNA复制和细胞周期控制的基因的表达在细胞周期进程中起关键作用。我们发现，E2 F1和E2 F2在小鼠中的组合损失导致在多个细胞谱系的造血发育中的深刻的细胞自主缺陷。E2 F2突变小鼠表现出红细胞成熟缺陷，与巨幼细胞性贫血患者中观察到的缺陷相当。重要的是，在E2 F1/E2 F2双敲除（DKO）小鼠中观察到的造血缺陷似乎是由造血祖细胞中的S期进展受阻引起的。在DKO B细胞成熟期间，超出大的前BII细胞阶段的分化是有缺陷的，推测是由于细胞周期退出失败，并且细胞经历凋亡。然而，凋亡似乎是成熟失败的结果，而不是原因。尽管造血祖细胞在S期积累，但E2 F1和E2 F2的联合缺失导致包括细胞周期蛋白A2在内的几种E2 F靶基因的表达和活性显著降低。我们的研究结果表明E2 F1和E2 F2在诱导EN靶基因中的特定作用，这有助于造血祖细胞的有效扩增和成熟。因此，E2 F1和E2 F2在细胞周期进程与分化的适当协调中发挥重要和冗余的作用，这是有效造血所必需的。
EN plays critical roles in cell cycle progression by regulating the expression of genes involved in nucleotide synthesis, DNA replication, and cell cycle control. We show that the combined loss of E2F1 and E2F2 in mice leads to profound cell-autonomous defects in the hematopoietic development of multiple cell lineages. E2F2 mutant mice show erythroid maturation defects that are comparable with those observed in patients with megaloblastic anemia. Importantly, hematopoietic defects observed in E2F1/E2F2 double-knockout (DKO) mice appear to result from impeded S phase progression in hematopoietic progenitor cells. During DKO B-cell maturation, differentiation beyond the large pre-BII-cell stage is defective, presumably due to failed cell cycle exit, and the cells undergo apoptosis. However, apoptosis appears to be the consequence of failed maturation, not the cause. Despite the accumulation of hematopoietic progenitor cells in S phase, the combined loss of E2F1 and E2F2 results in significantly decreased expression and activities of several E2F target genes including cyclin A2. Our results indicate specific roles for E2F1 and E2F2 in the induction of EN target genes, which contribute to efficient expansion and maturation of hematopoietic progenitor cells. Thus, E2F1 and E2F2 play essential and redundant roles in the proper coordination of cell cycle progression with differentiation which is necessary for efficient hematopoiesis.