Hypoxia inducible factor 2α (HIF2α) transcriptionally activates several genes in response to
hypoxia. Under normoxic conditions, it undergoes
oxygen-dependent degradation by the
prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) system. The presence of an
iron-responsive
element (IRE) within the
5' untranslated region of HIF2α
mRNA suggests a further
iron- and
oxygen-dependent mechanism for translational regulation of its expression via
iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively). We show here that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2α-dependent abnormalities in erythropoiesis and systemic
iron metabolism. Thus, 4- to 6-week-old IRP1(-/-) mice exhibit
splenomegaly and extramedullary hematopoiesis, which is corrected in older animals. These erythropoietic abnormalities are caused by translational de-repression of HIF2α
mRNA and subsequent accumulation of HIF2α, which induces expression of
erythropoietin (Epo). Increased levels of circulating Epo lead to
reticulocytosis,
polycythemia, and suppression of hepatic
hepcidin mRNA. This in turn promotes hyperferremia and
iron depletion in splenic macrophages due to unrestricted expression of
ferroportin. Our data demonstrate that IRP1 is the principal regulator of HIF2α mRNA translation in vivo and provide evidence that translational control of HIF2α expression dominates over PHD/VHL-mediated regulation of HIF2α stability in juvenile IRP1(-/-) mice.