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  • Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis.

Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis.

Genes & development (2015-12-19)
Zahra Kadri, Carine Lefevre, Olivier Goupille, Tipparat Penglong, Marine Granger-Locatelli, Suthat Fucharoen, Leila Maouche-Chretien, Philippe Leboulch, Stany Chretien
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.

MATERIALS
Product Number
Brand
Product Description

SAFC
Insulin, Human Recombinant, for research or for further manufacturing use, dry powder
Sigma-Aldrich
Lactate Dehydrogenase Activity Assay Kit, sufficient for 500 colorimetric tests
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Drabkin′s reagent, for the determination of hemoglobin
Sigma-Aldrich
(+)-Biotin N-hydroxysuccinimide ester, ≥98% (HPLC), powder
Sigma-Aldrich
Pioglitazone
Sigma-Aldrich
2-Chloroethyl acrylate, contains >100 ppm MEHQ as inhibitor, 97%
Sigma-Aldrich
Anti-GATA1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution