Regulation of transferrin receptor-1 mRNA by the interplay between IRE-binding proteins and miR-7/miR-141 in the 3'-IRE stem-loops.
Regulation of transferrin receptor-1 mRNA by the interplay between IRE-binding proteins and miR-7/miR-141 in the 3'-IRE stem-loops.
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DOI：
10.1261/rna.063941.117
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Tsuji Y
中科院分区：
文献类型：
--
作者：
Miyazawa M;Bogdan AR;Hashimoto K;Tsuji Y
细胞内铁是由铁转运和储存基因，如转铁蛋白受体-1（TfR 1）和铁蛋白的协调表达密切调控的。它们主要通过铁诱导铁调节蛋白（IRP）从TfR 1的3′-UTR（非翻译区）或铁蛋白mRNA的5′-UTR中的铁响应元件（IRE）解离，导致TfR 1 mRNA的不稳定和铁蛋白翻译阻断的释放来调节。因此，高铁通过TfR 1 mRNA降解减少铁转运，并通过铁蛋白翻译上调增加铁储存。然而，TfR 1 mRNA不稳定的分子机制，在响应铁仍然难以捉摸。在此，我们证明miR-7- 5 p和miR-141- 3 p靶向3′-TfR 1 IRES并下调TfR 1 mRNA和蛋白表达。相反，miR-7- 5 p和miR-141- 3 p microRNAs部分但显著阻断铁或IRP敲低诱导的TfR 1 mRNA下调，表明这些microRNAs和IRP之间的相互作用沿着另一种未表征的机制参与TfR 1 mRNA降解。使用3′-UTR TfR 1 IRE突变体的荧光素酶报告基因分析表明，IRE C和E分别是miR-7- 5 p和miR-141- 3 p的靶点。此外，在人胰腺癌患者样本中，miR-7表达与TfR 1 mRNA呈负相关。这些结果表明microRNA在IRP-IRE系统中的TfR 1调节中的作用。
Intracellular iron is tightly regulated by coordinated expression of iron transport and storage genes, such as transferrin receptor-1 (TfR1) and ferritin. They are primarily regulated by iron through iron-induced dissociation of iron-regulatory proteins (IRPs) from iron-responsive elements (IREs) in the 3′-UTR (untranslated region) of TfR1 or 5′-UTR of ferritin mRNA, resulting in destabilization of TfR1 mRNA and release of ferritin translation block. Thus high iron decreases iron transport via TfR1 mRNA degradation and increases iron storage via ferritin translational up-regulation. However, the molecular mechanism of TfR1 mRNA destabilization in response to iron remains elusive. Here, we demonstrate that miR-7-5p and miR-141-3p target 3′-TfR1 IREs and down-regulate TfR1 mRNA and protein expression. Conversely, miR-7-5p and miR-141-3p antagomiRs partially but significantly blocked iron- or IRP knockdown-induced down-regulation of TfR1 mRNA, suggesting the interplay between these microRNAs and IRPs along with involvement of another uncharacterized mechanism in TfR1 mRNA degradation. Luciferase reporter assays using 3′-UTR TfR1 IRE mutants suggested that the IREs C and E are targets of miR-7-5p and miR-141-3p, respectively. Furthermore, miR-7 expression was inversely correlated with TfR1 mRNA in human pancreatic adenocarcinoma patient samples. These results suggest a role of microRNAs in the TfR1 regulation in the IRP–IRE system.
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影响因子：
3
作者：
Daniels, Tracy R.;Bernabeu, Ezequiel;Rodriguez, Jose A.;Patel, Shabnum;Kozman, Maggie;Chiappetta, Diego A.;Holler, Eggehard;Ljubimova, Julia Y.;Helguera, Gustavo;Penichet, Manuel L.
通讯作者：
Penichet, Manuel L.
影响因子：
4
作者：
Feng S;Wang Y;Zhang R;Yang G;Liang Z;Wang Z;Zhang G
通讯作者：
Zhang G
影响因子：
29
作者：
Bayeva M;Khechaduri A;Puig S;Chang HC;Patial S;Blackshear PJ;Ardehali H
通讯作者：
Ardehali H
影响因子：
--
作者：
Kindrat I;Tryndyak V;de Conti A;Shpyleva S;Mudalige TK;Kobets T;Erstenyuk AM;Beland FA;Pogribny IP
通讯作者：
Pogribny IP
影响因子：
3.7
作者：
Byrne SL;Buckett PD;Kim J;Luo F;Sanford J;Chen J;Enns C;Wessling-Resnick M
通讯作者：
Wessling-Resnick M