Model for involvement of Stat5 in iron uptake. Left side shows that in iron-replete cells, IRP-1 is converted into cytosolic aconitase (catalyzes isomerization of citrate to isocitrate in the citric acid cycle and exhibits no mRNA-binding affinity; green asterisk) and IRP-2 is degraded. Therefore, both cannot bind to IREs in the 3′UTR of TfR-1 mRNA. Free unprotected IREs in turn enhance degradation rates of TfR-1 mRNA, resulting in reduced iron uptake. In iron-depleted cells, IRP-1 and IRP-2 bind to the respective IREs, thereby stabilizing TfR-1 mRNA, resulting in increased iron uptake. The right side shows Stat5^−/−. Due to lack of Stat5, basal TfR-1 transcript abundance is reduced in comparison to wt cells. In addition, Stat5 deficiency further results in decreased levels of IRP-2 and, in consequence, a reduction of binding to IREs in the 3′UTR of TfR-1 mRNA and decreased transcript stabilization. Together, this constitutes a double-negative effect on erythroid iron uptake even in a situation of high iron demand, as in iron-deficiency anemia. *P < .05; **P < .01.