Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo
Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo
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DOI：
10.1126/science.1103786
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发表时间：
2004-12-17
期刊：
影响因子：
56.9
通讯作者：
Rouault, TA
中科院分区：
文献类型：
--
作者：
Meyron-Holtz, EG;Ghosh, MC;Rouault, TA
铁调节蛋白（IRPs）转录后调节转铁蛋白受体、铁蛋白和其他铁代谢蛋白的表达。尽管这两种IRPs都可以调节相同靶基因的表达，但IRP2（-/-）小鼠显著失调铁代谢并发生神经变性，而IRP1（-/-）小鼠则没有。我们发现IRP2（-/-）细胞在与生理组织浓度相当的3 - 6%的氧气中培养时，铁代谢失调，但在21%的氧气中却没有，这一浓度激活了IRP1并使其替代了IRP2。因此，IRP2在哺乳动物铁稳态调节中起主导作用，因为它单独记录铁浓度并在生理氧张力下调节其rna结合活性。
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.