Effects of iron regulatory protein regulation on iron homeostasis during hypoxia.
Iron regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that affect the translation and stabilization of specific mRNAs by binding to stem-loop structures known as iron responsive elements (IREs). IREs are found in the 5'-untranslated region (UTR) of ferritin (Ft) and mitochondrial aconitase (m-Aco) mRNAs, and in the 3'-UTR of transferrin receptor (TfR) and divalent metal transporter-1 (DMT1) mRNAs. Our previous studies show that besides iron, IRPs are regulated by hypoxia. Here we describe the consequences of IRP regulation and show that iron homeostasis is regulated in 2 phases during hypoxia: an early phase where IRP1 RNA-binding activity decreases and iron uptake and Ft synthesis increase, and a late phase where IRP2 RNA-binding activity increases and iron uptake and Ft synthesis decrease. The increase in iron uptake is independent of DMT1 and TfR, suggesting an unknown transporter. Unlike Ft, m-Aco is not regulated during hypoxia. During the late phase of hypoxia, IRP2 RNA-binding activity increases, becoming the dominant regulator responsible for decreasing Ft synthesis. During reoxygenation (ReO2), Ft protein increases concomitant with a decrease in IRP2 RNA-binding activity. The data suggest that the differential regulation of IRPs during hypoxia may be important for cellular adaptation to low oxygen tension.
Schneider
Brian D
BD
Program in Human Molecular Biology and Genetics, and Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Leibold
Elizabeth A
EA
D002460:Cell Line; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D013997:Time Factors; D014168:Transferrin / Q000096:biosynthesis
D035925:Iron-Regulatory Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D010100:Oxygen