Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo

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Science  17 Dec 2004:
Vol. 306, Issue 5704, pp. 2087-2090
DOI: 10.1126/science.1103786

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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.

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