Regulation of transferrin receptor 2 protein levels by transferrin
Regulation of transferrin receptor 2 protein levels by transferrin
复制标题
DOI：
10.1182/blood-2004-06-2481
复制
发表时间：
2004-12-15
期刊：
影响因子：
20.3
通讯作者：
Wessling-Resnick, M
中科院分区：
文献类型：
--
作者：
Robb, A;Wessling-Resnick, M
转铁蛋白受体2（TfR 2）在铁稳态中起着关键作用，因为携带TFR 2基因失能突变的患者患有血色病。在这项研究中，铁响应调节TfR 2在蛋白质水平进行了检查，在体外和体内。全转铁蛋白（holotransferrin，holoTf）诱导HepG 2细胞TfR 2蛋白表达上调，且呈时间和剂量依赖性。ApoTf或高铁治疗与非Tf结合的铁未能引起类似的效果，这表明TfR 2调节反映了铁结合配体的相互作用。肝脏TfR 2蛋白水平也反映了对体内铁状态变化的适应性反应。肝脏TfR 2蛋白水平下调和上调大鼠分别喂养缺铁和高铁饮食。TfR 2也在Hfe（-/-）小鼠中上调，Hfe（-/-）小鼠是一种显示肝脏铁负荷的动物模型。相反，尽管肝脏铁超载，低转铁蛋白血症小鼠的TfR 2水平降低，支持受体的调节依赖于Tf的观点。这一想法通过β-地中海贫血小鼠中TfR 2的上调得到证实，β-地中海贫血小鼠与低转铁蛋白血症小鼠一样，贫血并引起铁负荷，但具有功能性Tf。基于这些综合结果，我们假设TfR 2作为铁状态的传感器，使得受体水平反映Tf饱和度。(C)2004年，美国血液学会。
Transferrin receptor 2 (TfR2) plays a critical role in iron homeostasis because patients carrying disabling mutations in the TFR2 gene suffer from hemochromatosis. In this study, iron-responsive regulation of TfR2 at the protein level was examined in vitro and in vivo. HepG2 cell TfR2 protein levels were up-regulated after exposure to holotransferrin (holoTf) in a time- and dose-responsive manner. ApoTf or high-iron treatment with non-Tf-bound iron failed to elicit similar effects, suggesting that TfR2 regulation reflects interactions of the iron-bound ligand. Hepatic TfR2 protein levels also reflected an adaptive response to changing iron status in vivo. Liver TfR2 protein levels were down- and up-regulated in rats fed an iron-deficient and a high-iron diet, respectively. TfR2 was also up-regulated in Hfe(-/-) mice, an animal model that displays liver iron loading. In contrast, TfR2 levels were reduced in hypotransferrinemic mice despite liver iron overload, supporting the idea that regulation of the receptor is dependent on Tf. This idea is confirmed by up-regulation of TfR2 in beta-thalassemic mice, which, like hypotransferrinemic mice, are anemic and incur iron loading, but have functional Tf. Based on these combined results, we hypothesize that TfR2 acts as a sensor of iron status such that receptor levels reflect Tf saturation. (C) 2004 by The American Society of Hematology.