Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo.
The iron-regulatory proteins (IRPs) posttranscriptionally regulate expression of transferrin receptor, ferritin, and other iron metabolism proteins. Although both IRPs can regulate expression of the same target genes, IRP2-/- mice significantly misregulate iron metabolism and develop neurodegeneration, whereas IRP1-/- mice are spared. We found that IRP2-/- cells misregulated iron metabolism when cultured in 3 to 6% oxygen, which is comparable to physiological tissue concentrations, but not in 21% oxygen, a concentration that activated IRP1 and allowed it to substitute for IRP2. Thus, IRP2 dominates regulation of mammalian iron homeostasis because it alone registers iron concentrations and modulates its RNA-binding activity at physiological oxygen tensions.
Meyron-Holtz
Esther G
EG
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Ghosh
Manik C
MC
Rouault
Tracey A
TA
D000818:Animals; D002478:Cells, Cultured; D005293:Ferritins / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000502:physiology*; D012313:RNA / Q000378:metabolism; D011990:Receptors, Transferrin / Q000096:biosynthesis / Q000378:metabolism; D020218:Response Elements; D013154:Spleen / Q000166:cytology
D016877:Oxidants; D011990:Receptors, Transferrin; D012313:RNA; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D010100:Oxygen