Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts
Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts
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DOI：
10.1128/mcb.01118-07
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发表时间：
2007-12-01
影响因子：
5.3
通讯作者：
Macleod, Kay F.
中科院分区：
文献类型：
--
作者：
Dirlam, Alexandra;Spike, Benjamin T.;Macleod, Kay F.
通过评估不受调控的E2F活性对Rb缺失小鼠红细胞缺陷的贡献，我们已经确定E2F -2在终末期红细胞中上调，我们表明它是主要的与prb相关的E2F，并且在关键靶基因启动子中检测到主要的E2F。与其表达模式一致，E2f-2缺失恢复了Rb零红细胞的终末红细胞成熟，包括去核能力。尽管胎盘发育存在持续缺陷，但E2f-2的缺失也延长了Rb缺失小鼠的寿命，这表明分化红母细胞中E2f-2活性的失调有助于Rb缺失小鼠的过早死亡。我们发现，当野生型红母细胞退出细胞周期时，Rb null红母细胞在分化过程中进入S期的异常行为受到E2f-2缺失的抑制。E2f-2缺失在野生型和Rb阴性红母细胞中均诱导细胞周期阻滞，并与DNA双链断裂增加有关。这些结果暗示了E2f-2在Rb null红母细胞中观察到的细胞周期缺陷中的失调，并揭示了E2f-2在终末红细胞分化中的新作用。E2f-2在红细胞生成中的组织限制性作用的鉴定突出了E2f转录因子在细胞生长和分化中的非冗余性。
By assessing the contribution of deregulated E2F activity to erythroid defects in Rb null mice, we have identified E2f-2 as being upregulated in end-stage red cells, where we show it is the major pRb-associated E2f and the predominant E2f detected at key target gene promoters. Consistent with its expression pattern, E2f-2 loss restored terminal erythroid maturation to Rb null red cells, including the ability to undergo enucleation. Deletion of E2f-2 also extended the life span of Rb null mice despite persistent defects in placental development, indicating that deregulated E2f-2 activity in differentiating erythroblasts contributes to the premature lethality of Rb null mice. We show that the aberrant entry of Rb null erythroblasts into S phase at times in differentiation when wild-type erythroblasts are exiting the cell cycle is inhibited by E2f-2 deletion. E2f-2 loss induced cell cycle arrest in both wild-type and Rb null erythroblasts and was associated with increased DNA double-strand breaks. These results implicate deregulated E2f-2 in the cell cycle defects observed in Rb null erythroblasts and reveal a novel role for E2f-2 during terminal red blood cell differentiation. The identification of a tissue-restricted role for E2f-2 in erythropoiesis highlights the nonredundant nature of E2f transcription factor activities in cell growth and differentiation.