The roles of hypoxia-inducible Factor-1 and iron regulatory protein 1 in iron uptake induced by acute hypoxia.
The roles of hypoxia-inducible Factor-1 and iron regulatory protein 1 in iron uptake induced by acute hypoxia.
复制标题
缺氧诱导因子1和铁调节蛋白1在急性缺氧诱导的铁摄取中的作用。
DOI：
10.1016/j.bbrc.2018.10.185
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhu Li
中科院分区：
文献类型：
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作者：
Yang Lei;Wang Dan;Wang Xue Ting;Lu Ya Peng;Zhu Li
背景信息二价金属转运蛋白1（DMT 1）和转铁蛋白受体（TfR 1）是细胞铁摄取的重要蛋白。这些蛋白质在其5 '调控区具有缺氧反应元件（HRE），在缺氧条件下受缺氧诱导因子1α（HIF-1α）的转录调控。此外，铁调节蛋白1（IRP 1）调节DMT 1和TfR 1通过结合铁响应元件（IRES）存在于其mRNA中，以控制细胞铁homeostasis.ResultsHere，我们探讨了急性缺氧对铁摄取的影响。急性缺氧时，DMT 1（+IRE）和TfR 1可促进亚铁离子的摄取。荧光素酶活性分析显示，DMT 1和TfR 1的功能性HRE增加。然而，它们的IRES依赖的荧光素酶活性同时降低。TfR 1和DMT 1（+IRE）mRNA的稳定性在急性缺氧条件下受到抑制。沉默IRP 1可抑制TfR 1和DMT 1（+IRE）的mRNA水平。与此形成鲜明对比的是，HIF-1α过表达增强了TfR 1和DMT 1（+IRE）的mRNA水平，从而逆转了IRP 1对两者的抑制。HIF-1α下调可抑制低氧诱导的TfR 1和DMT 1（+IRE）表达的增加，而进一步下调低氧诱导的IRP 1表达对这两种蛋白的表达无明显影响。缺氧以时间依赖性方式上调Ferrtin-L的蛋白表达，但缺氧条件下IRP 1沉默或过表达无差异。结论HIF-1/HRE系统可能在缺氧诱导的铁摄取中起主要作用。
Background InformationDivalent metal transporter 1 (DMT1) and transferrin receptor (TfR1) are vital proteins for cellular iron uptake. These proteins have hypoxia-responsive elements (HREs) in their 5‘-regulatory region, and they are regulated by hypoxia-inducible factor 1α (HIF-1α) transcriptionally under hypoxic condition. Besides, iron regulatory protein 1 (IRP1) regulates DMT1 and TfR1 by binding to iron-responsive elements (IREs) present in their mRNAs to control cellular iron homeostasis.ResultsHere, we explored the effect of acute hypoxia on iron uptake. Ferrous iron uptake was elevated by DMT1(+IRE) and TfR1 under acute hypoxia. The luciferase activity analysis revealed that the functional HREs of DMT1 and TfR1 were increased. However, their IREs-dependent luciferase activities were reduced simultaneously. The mRNA stability of TfR1 and DMT1(+IRE) was suppressed under acute hypoxia. The mRNA levels of TfR1 and DMT1(+IRE) were restrain by silencing IRP1. In sharp contrast, HIF-1α overexpression enhanced the mRNA levels of TfR1 and DMT1(+IRE), which reversed the inhibition of IRP1 on both. HIF-1α konckdown suppressed the hypoxia-induced increase expression of TfR1 and DMT1(+IRE), whereas both proteins had little change when further decreased the IRP1 expression under hypoxia. Hypoxia upregulated the protein expression of Ferrtin-L in a time-dependent manner, yet there was no different when IRP1 silencing or overexperssion under hypoxia. The lactate dehydrogenase (LDH) release induced by hypoxia was increased by TfR1 siRNA silence.ConclusionsWe propose that HIF-1/HRE system might play a principal part in hypoxia induced iron uptake.