Differential Regulation of Foxo3a Target Genes in Erythropoiesis

Abstract

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.

MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis

“…These results indicate that miR-223 exerts its inhibitory role in erythroid cells through LMO2, although we cannot exclude the possibility that miR-223 may also target other genes relevant for erythropoiesis. This evidence is supported by computational analysis which indicate that miR-223 might also target FOXO3A 34,35 and Sp3, 36 two transcription factors involved in erythroid differentiation.…”

Hydroxyurea responsiveness in -thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

“…43,44 ARG2 and HIPK2 are known FOXO3 target genes. 45 These genes were all consistently up-regulated in R-HEPs compared to NR-HEPs, and further up-regulated upon treatment with HU in both groups (Online Supplementary Figure S3B). Notably, expression levels of ARG1 and ARG2 were higher in the untreated R-HEP cultures than in HU-treated NR-HEP cultures and may have a role in protecting R-HEPs from HU-induced cell death.…”

“…A number of FOXO3 target genes are also up-regulated, for example HIPK2 and BTG1 (Online Supplementary Table S3). 45 Interestingly, the function of stress-induced FOXO3 protein is not to induce cell death, but to increase the potential of cells to prevent and repair oxidative damage and to slow down the cell cycle to allow DNA repair before replication.…”

miR-451 protects against erythroid oxidant stress by repressing 14-3-3ζ

“…(E) Loss of miR-144/451 inhibits erythroid FoxO3 activity. The X-axis indicates genes that were induced (n = 50) or repressed (n = 172) after activation of FoxO3 in erythroid cells, according to a previous study (Bakker et al 2007). The bar marked ''neither'' represents the entire cohort of expressed mRNAs detected in the current study minus FoxO3-induced and FoxO3-repressed genes detected by Bakker et al (2007).…”