Differential regulation of Foxo3a target genes in erythropoiesis
Differential regulation of Foxo3a target genes in erythropoiesis
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DOI：
10.1128/mcb.01662-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
von Lindern, Marieke
中科院分区：
文献类型：
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作者：
Bakker, Walbert J.;van Dijk, Thamar B.;von Lindern, Marieke
干细胞因子(SCF)和促红细胞生成素(EPO)的协同作用需要诱导红系祖细胞的更新分裂，而向成熟红细胞的分化只需要EPO的存在。EPO和SCF激活共同的信号通路，如蛋白激酶B(PKB)的激活以及随后的Foxo3a的磷酸化和失活。相比之下，只有EPO激活Stat5。Foxo3a和Stat5均促进红系分化。为了了解SCF和EPO在维持红系发育过程中更新和分化之间的平衡方面的相互作用，我们研究了EPO和SCF对Foxo3a靶标的差异调控。表达谱显示，Foxo3a靶标的一个子集不被EPO抑制，而是被激活。其中一个基因是Cited2。研究了EPO/Foxo3a诱导的Cited2的转录调控，并与EPO抑制的Foxo3a靶标Btg1进行了比较。我们发现，作为对EPO的反应，所谓的生长抑制因子Foxo3a与核中据称的生长刺激因子Stat5有关，这是EPO诱导Cited2表达所必需的。相反，Btg1的表达是由Foxo3a与依赖环AMP和Jun激酶的Creb家族成员共同控制的。因此，Foxo3a不仅是PKB的效应者，而且在红细胞生成过程中整合不同的信号来调节基因的表达。
The cooperation of stem cell factor (SCF) and erythropoietin (Epo) is required to induce renewal divisions in erythroid progenitors, whereas differentiation to mature erythrocytes requires the presence of Epo only. Epo and SCF activate common signaling pathways such as the activation of protein kinase B (PKB) and the subsequent phosphorylation and inactivation of Foxo3a. In contrast, only Epo activates Stat5. Both Foxo3a and Stat5 promote erythroid differentiation. To understand the interplay of SCF and Epo in maintaining the balance between renewal and differentiation during erythroid development, we investigated differential Foxo3a target regulation by Epo and SCF. Expression profiling revealed that a subset of Foxo3a targets was not inhibited but was activated by Epo. One of these genes was Cited2. Transcriptional control of Epo/Foxo3a-induced Cited2 was studied and compared with that of the Epo-repressed Foxo3a target Btg1. We show that in response to Epo, the allegedly growth-inhibitory factor Foxo3a associates with the allegedly growth-stimulatory factor Stat5 in the nucleus, which is required for Epo-induced Cited2 expression. In contrast, Btg1 expression is controlled by the cooperation of Foxo3a with cyclic AMP- and Jun kinase-dependent Creb family members. Thus, Foxo3a not only is an effector of PKB but also integrates distinct signals to regulate gene expression in erythropoiesis.