Foxo3 is required for the regulation of oxidative stress in erythropoiesis

Abstract

Erythroid cells accumulate hemoglobin as they mature and as a result are highly prone to oxidative damage. However, mechanisms of transcriptional control of antioxidant defense in erythroid cells have thus far been poorly characterized. We observed that animals deficient in the forkhead box O3 (Foxo3) transcription factor died rapidly when exposed to erythroid oxidative stress-induced conditions, while wild-type mice showed no decreased viability. In view of this striking finding, we investigated the potential role of Foxo3 in the regulation of ROS in erythropoiesis. Foxo3 expression, nuclear localization, and transcriptional activity were all enhanced during normal erythroid cell maturation. Foxo3-deficient erythrocytes exhibited decreased expression of ROS scavenging enzymes and had a ROS-mediated shortened lifespan and evidence of oxidative damage. Furthermore, loss of Foxo3 induced mitotic arrest in erythroid precursor cells, leading to a significant decrease in the rate of in vivo erythroid maturation. We identified ROS-mediated upregulation of p21 CIP1/WAF1/Sdi1 (also known as Cdkn1a) as a major contributor to the interference with cell cycle progression in Foxo3-deficient erythroid precursor cells. These findings establish an essential nonredundant function for Foxo3 in the regulation of oxidative stress, cell cycle, maturation, and lifespan of erythroid cells. These results may have an impact on the understanding of human disorders in which ROS play a role.

The role of autophagy in neonatal tissues: Just a response to amino acid starvation?

“…27 FoxO3-deficient hematopoietic stem cells show marked increase in ROS due to decreased expression of ROS scavenging enzymes and evidence of free radical damage. 28 Similar results were obtained with the conditional deletion of FoxO1, FoxO3 and FoxO4 in the adult hematopoietic system. 29 The effect of oxidative stress on FoxO can be mediated by the protein kinase Mst1 which phosphorylates FoxO proteins at a conserved site within the forkhead domain, thus disrupting their interaction with 14-3-3 proteins and promoting FoxO nuclear translocation and activation.…”

Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals

“…S5). Akt-mediated signaling was previously demonstrated to be an important regulator in defense against oxidative stress (25). Interestingly, phospho-Akt level of erythroblasts was excessively up-regulated in PKOs but not DKOs (Fig.…”

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

“…Among the four FOXO genes, FOXO3 has been the most widely investigated. As a transcription factor, FOXO3 regulates expression of several target genes that participate in a series of cellular processes and respond to various cellular stresses (4)(5)(6)(7)(8). Alternatively, different cellular stresses cause variant statuses of posttranslational modifications of FOXO3, such as phosphorylation, ubiquitination, acetylation, and methylation, which in turn regulate the stability or activity of FOXO3 (9)(10)(11)(12)(13)(14).…”