E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation
E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation
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DOI：
10.1182/blood-2005-09-008656
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发表时间：
2006-08-01
期刊：
影响因子：
20.3
通讯作者：
Humbert, Patrick Orson
中科院分区：
文献类型：
--
作者：
Kinross, Kathryn M.;Clark, Allison J.;Humbert, Patrick Orson
E2F蛋白是协调细胞周期进展和退出所需的转录程序的主要调节因子。特别是，E2f4被认为是主要通过其转录抑制特性调控细胞周期退出的主要家族成员。我们之前已经表明，UN-/-小鼠表现出明显的大细胞性贫血，暗示E2f4在红细胞生成的调节中。然而，这些研究无法区分E2f4是分化、存活还是增殖控制所必需的。在这里，我们描述了E2f4在促进红细胞增殖中的一种新功能。我们发现E2f4的缺失导致体内胎儿红细胞室的扩张受损，这与细胞周期进展受损和红细胞增殖减少有关。与这些观察结果一致，cDNA微阵列分析显示细胞周期控制基因是EV4-1- FLs中下调的主要基因之一，并且我们提供的证据表明E2f4可能直接调控这些基因的转录表达。我们得出结论，EV4（-/-）小鼠的大细胞性贫血主要是由于细胞增殖受损，E2f4在胎儿红细胞生成中的主要作用是促进细胞周期进展和细胞凋亡
The E2F proteins are major regulators of the transcriptional program required to coordinate cell cycle progression and exit. In particular, E2f4 has been proposed to be the principal family member responsible for the regulation of cell cycle exit chiefly through its transcriptional repressive properties. We have previously shown that UN-/- mice display a marked macrocytic anemia implicating E2f4 in the regulation of erythropoiesis. However, these studies could not distinguish whether E2f4 was required for differentia-tion, survival, or proliferation control. Here, we describe a novel function for E2f4 in the promotion of erythroid proliferation. We show that loss of E2f4 results in an impaired expansion of the fetal erythroid compartment in vivo that is associated with impaired cell cycle progression and decreased erythroid proliferation. Consistent with these observations, cDNA microarray analysis reveals cell cycle control genes as one of the major class of genes down-regulated in EV4-1- FLs, and we provide evidence that E2f4 may directly regulate the transcriptional expression of a number of these genes. We conclude that the macrocytic anemia of EV4(-/-) mice results primarily from impaired cellular proliferation and that the major role of E2f4 in fetal erythropoiesis is to promote cell cycle progression and cellular