Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1.
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 Stat5 in erythropoiesis remained puzzling, however, since the first Stat5-deficient 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 antiapoptotic proteins Bcl-x(L) and Mcl-1 followed by enhanced apoptosis. Moreover, transferrin receptor-1 (TfR-1) cell surface levels on erythroid cells were decreased more than 2-fold on erythroid 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.
Kerenyi
Marc A
MA
Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria.
Grebien
Florian
F
Gehart
Helmuth
H
Schifrer
Manfred
M
Artaker
Matthias
M
Kovacic
Boris
B
Beug
Hartmut
H
Moriggl
Richard
R
Müllner
Ernst W
EW
D018798:Anemia, Iron-Deficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001693:Biological Transport, Active; D020964:Embryo Loss; D041905:Erythroid Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D035942:Iron Regulatory Protein 2 / Q000378:metabolism*; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D050799:STAT5 Transcription Factor; C480029:Tfrc protein, mouse; D007501:Iron; D035942:Iron Regulatory Protein 2