title: FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis.
abstract: Ineffective erythropoiesis is observed in many erythroid disorders including β-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3(-/-) erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of β-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.
authors: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, 10029.
authors: Xin
authors: X
authors: Zhang
authors: Genís
authors: G
authors: Campreciós
authors: Pauline
authors: P
authors: Rimmelé
authors: Raymond
authors: R
authors: Liang
authors: Safak
authors: S
authors: Yalcin
authors: Sathish Kumar
authors: SK
authors: Mungamuri
authors: Jeffrey
authors: J
authors: Barminko
authors: Valentina
authors: V
authors: D'Escamard
authors: Margaret H
authors: MH
authors: Baron
authors: Carlo
authors: C
authors: Brugnara
authors: Dmitri
authors: D
authors: Papatsenko
authors: Stefano
authors: S
authors: Rivella
authors: Saghi
authors: S
authors: Ghaffari
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017086:beta-Thalassemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases