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Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo
Esther G. Meyron-Holtz,Manik C. Ghosh,Tracey A. Rouault*
The iron-regulatory proteins (IRPs) posttranscriptionally regulateexpression of transferrin receptor, ferritin, and other ironmetabolism proteins. Although both IRPs can regulate expressionof the same target genes, IRP2–/– mice significantlymisregulate iron metabolism and develop neurodegeneration, whereasIRP1–/– 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 andallowed it to substitute for IRP2. Thus, IRP2 dominates regulationof mammalian iron homeostasis because it alone registers ironconcentrations and modulates its RNA-binding activity at physiologicaloxygen tensions.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
* To whom correspondence should be addressed. E-mail: trou{at}helix.nih.gov
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