Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency

M Sanchez, B Galy, MU Muckenthaler… - Nature structural & …, 2007 - nature.com
Nature structural & molecular biology, 2007nature.com
Hypoxia stimulates erythropoiesis, the major iron-utilization pathway. We report the
discovery of a conserved, functional iron-responsive element (IRE) in the 5′ untranslated
region of the messenger RNA encoding endothelial PAS domain protein-1, EPAS1 (also
called hypoxia-inducible factor-2α, HIF2α). Via this IRE, iron regulatory protein binding
controls EPAS1 mRNA translation in response to cellular iron availability. Our results
uncover a regulatory link that permits feedback control between iron availability and the …
Abstract
Hypoxia stimulates erythropoiesis, the major iron-utilization pathway. We report the discovery of a conserved, functional iron-responsive element (IRE) in the 5′ untranslated region of the messenger RNA encoding endothelial PAS domain protein-1, EPAS1 (also called hypoxia-inducible factor-2α, HIF2α). Via this IRE, iron regulatory protein binding controls EPAS1 mRNA translation in response to cellular iron availability. Our results uncover a regulatory link that permits feedback control between iron availability and the expression of a key transcription factor promoting iron utilization. They also show that an IRE that is structurally distinct from, for example, the ferritin mRNA IRE and that has been missed by in silico approaches, can mediate mechanistically similar responses.
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