title: Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis.
abstract: Tight coordination of cell proliferation and differentiation is central to red blood cell formation. Erythropoietin controls the proliferation and survival of red blood cell precursors, while variations in GATA-1/FOG-1 complex composition and concentrations drive their maturation. However, clear evidence of cross-talk between molecular pathways is lacking. Here, we show that erythropoietin activates AKT, which phosphorylates GATA-1 at Ser310, thereby increasing GATA-1 affinity for FOG-1. In turn, FOG-1 displaces pRb/E2F-2 from GATA-1, ultimately releasing free, proproliferative E2F-2. Mice bearing a Gata-1(S310A) mutation suffer from fatal anemia when a compensatory pathway for E2F-2 production involving insulin-like growth factor-1 (IGF-1) signaling is simultaneously abolished. In the context of the GATA-1(V205G) mutation resulting in lethal anemia, we show that the Ser310 cannot be phosphorylated and that constitutive phosphorylation at this position restores partial erythroid differentiation. This study sheds light on the GATA-1 pathways that synchronize cell proliferation and differentiation for tissue homeostasis.
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France;
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kadri
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France;
authors.forename: Carine
authors.initials: C
authors.lastname: Lefevre
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Goupille
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France; Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, 73170 Nakhon Pathom, Thailand;
authors.forename: Tipparat
authors.initials: T
authors.lastname: Penglong
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France;
authors.forename: Marine
authors.initials: M
authors.lastname: Granger-Locatelli
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, 73170 Nakhon Pathom, Thailand;
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France; Institut National de la Santé et de la Recherche Médicale, 75013 Paris, France;
authors.forename: Leila
authors.initials: L
authors.lastname: Maouche-Chretien
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France; Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, 73170 Nakhon Pathom, Thailand; Genetics Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.affiliation: Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France; UMR-E 007, Université Paris-Saclay, 91400 Orsay, France; Institut National de la Santé et de la Recherche Médicale, 75013 Paris, France;
authors.forename: Stany
authors.initials: S
authors.lastname: Chretien
mesh_terms: D000743:Anemia, Hemolytic / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D041905:Erythroid Cells / Q000166:cytology*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt
keywords: GATA-1; IGF-1; differentiation; erythropoiesis; proliferation; signalization