Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1

Abstract

Erythropoiesis strictly depends on signal transduction through the erythropoietin receptor (EpoR)-Janus kinase 2 (Jak2)-signal transducer and activator of transcription 5 (Stat5) axis, regulating proliferation, differentiation, and survival. The exact role of the transcription factor StatS In erythropoiesis remained puzzling, however, since the first Stat5-deflclent mice carried a hypomorphic Stat5 allele, impeding full phenotypical analysis. Using mice completely lacking Stat5- displaying early lethality-we demonstrate that these animals suffer from microcytic anemia due to reduced expression of the antiapoptotlc proteins Bcl-xL and Mcl-1 followed by enhanced apoptosis. Moreover, transferrin receptor-1 (TfR-1) cell surface levels on erythrold cells were decreased more than 2-fold on erythrold cells of Stat5-/- animals. This reduction could be attributed to reduced transcription of TfR-1 mRNA and iron regulatory protein 2 (IRP-2), the major translational regulator of TfR-1 mRNA stability In erythroid cells. Both genes were demonstrated to be direct transcriptional targets of Stat5. This establishes an unexpected mechanistic link between EpoR/Jak/Stat signaling and Iron metabolism, processes absolutely essential for erythropoiesis and life. © 2008 by The American Society of Hematology.