Foxo3 is required for the regulation of oxidative stress in erythropoiesis
Dragan Marinkovic, … , Tara Huber, Saghi Ghaffari
Dragan Marinkovic, … , Tara Huber, Saghi Ghaffari
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2133-2144. https://doi.org/10.1172/JCI31807.
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Research Article

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 p21CIP1/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.

Authors

Dragan Marinkovic, Xin Zhang, Safak Yalcin, Julia P. Luciano, Carlo Brugnara, Tara Huber, Saghi Ghaffari

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Figure 3

ROS induced shortened erythrocyte lifespan in Foxo3–/– mice.

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ROS induced shortened erythrocyte lifespan in Foxo3–/– mice. ...
(A) In vivo NAC therapy improves the lifespan of erythrocytes in Foxo3–/– mice. WT and Foxo3–/– mice were treated intraperitoneally with NAC (100 mg/kg) or PBS 3 times a week; after 3 weeks, erythrocytes were biotinylated in vivo and erythrocyte lifespan measured as in Figure 2, while NAC (or PBS) treatment continued for another 3 weeks. (B) Reticulocyte index was measured after 6 weeks in all mice. One of 2 independent experiments is shown. Results represent mean ± SEM, n = 6 per group; *P < 0.05.