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. Author manuscript; available in PMC: 2019 Mar 1.
Published in final edited form as: Blood Rev. 2017 Oct 3;32(2):130–143. doi: 10.1016/j.blre.2017.10.001

Figure 2. The role of FOXO3-mTOR cross talk in β-thalassemia.

Figure 2

a. EPO stimulation promotes activation of phosphoinositide 3-kinase (PI3K). PI3K phosphorylates AKT kinase, which phosphorylates FOXO3 and induces its nuclear export, resulting in inhibition of FOXO3 transcriptional activity. AKT kinase also phosphorylates and regulates mammalian target of rapamycin (mTOR) kinase. b. In FOXO3 deficient mice (FOXO3 −/−) lack of FOXO3 increases activation of JAK2/AKT/mTOR signaling. Impaired antioxidant response, due to FOXO3 deficiency, increases ROS that partially mediate hyperactivation of JAK2/AKT/mTOR signaling. FOXO3 deficient erythroblasts exhibit abnormalities similar to IE. c. Inhibition of mTOR signaling by rapamycin in TI mice, improved the anemia, implicating mTOR signaling in the pathogenesis of IE. Resveratrol inhibits AKT kinase and increases activation of FOXO3. Resveratrol treatment of TI mice accelerated erythroblast maturation and decreased IE.