The IRP/IRE system in vivo: insights from mouse models.
The IRP/IRE system in vivo: insights from mouse models.
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DOI：
10.3389/fphar.2014.00176
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发表时间：
2014
影响因子：
5.6
通讯作者：
Pantopoulos K
中科院分区：
文献类型：
--
作者：
Wilkinson N;Pantopoulos K
铁调节蛋白1和2（IRP 1和IRP 2）转录后控制几种编码铁、氧和能量代谢蛋白的mRNA的表达。其机制涉及它们与靶mRNA非翻译区中的铁响应元件（IRE）结合，从而控制mRNA翻译或稳定性。IRP 2仅作为RNA结合蛋白发挥作用，而IRP 1作为RNA结合蛋白或胞质乌头酸酶发挥作用。早期在培养细胞中的实验确定了IRP在调节细胞铁代谢中的关键作用。最近，在具有全局或局部Irp 1和/或Irp 2缺陷的小鼠模型中的研究揭示了IRP在系统性铁稳态背景下的新生理功能。因此，IRP 1通过控制缺氧诱导因子2α（HIF 2 α）mRNA的翻译成为红细胞生成和铁吸收的关键调节因子，而IRP 2似乎分别通过调节转铁蛋白受体1（TfR 1）和5-氨基乙酰丙酸合成酶2（ALAS 2）mRNA的表达来主导红系祖细胞中铁吸收和血红素生物合成的控制。在小鼠中靶向破坏Irp 1或Irp 2与不同的表型异常相关。因此，Irp 1 −/−小鼠会出现红细胞增多症和肺动脉高压，而Irp 2 −/−小鼠会出现小细胞性贫血、肠道和肝脏铁过载以及神经系统缺陷。Irp 1和Irp 2的联合破坏与生命不相容，并导致早期胚胎死亡。具有肠或肝脏特异性两种Irps破坏的小鼠在出生时是可行的，但随后分别由于吸收不良或肝功能衰竭而死亡。在肠中缺乏两种Irps的成年小鼠表现出饮食铁吸收的严重缺陷，这是由于铁蛋白mRNA翻译的去抑制引起的“粘膜阻塞”。在此，我们讨论了IRE/IRP调节系统的生理功能。
Iron regulatory proteins 1 and 2 (IRP1 and IRP2) post-transcriptionally control the expression of several mRNAs encoding proteins of iron, oxygen and energy metabolism. The mechanism involves their binding to iron responsive elements (IREs) in the untranslated regions of target mRNAs, thereby controlling mRNA translation or stability. Whereas IRP2 functions solely as an RNA-binding protein, IRP1 operates as either an RNA-binding protein or a cytosolic aconitase. Early experiments in cultured cells established a crucial role of IRPs in regulation of cellular iron metabolism. More recently, studies in mouse models with global or localized Irp1 and/or Irp2 deficiencies uncovered new physiological functions of IRPs in the context of systemic iron homeostasis. Thus, IRP1 emerged as a key regulator of erythropoiesis and iron absorption by controlling hypoxia inducible factor 2α (HIF2α) mRNA translation, while IRP2 appears to dominate the control of iron uptake and heme biosynthesis in erythroid progenitor cells by regulating the expression of transferrin receptor 1 (TfR1) and 5-aminolevulinic acid synthase 2 (ALAS2) mRNAs, respectively. Targeted disruption of either Irp1 or Irp2 in mice is associated with distinct phenotypic abnormalities. Thus, Irp1−/− mice develop polycythemia and pulmonary hypertension, while Irp2−/− mice present with microcytic anemia, iron overload in the intestine and the liver, and neurologic defects. Combined disruption of both Irp1 and Irp2 is incombatible with life and leads to early embryonic lethality. Mice with intestinal- or liver-specific disruption of both Irps are viable at birth but die later on due to malabsorption or liver failure, respectively. Adult mice lacking both Irps in the intestine exhibit a profound defect in dietary iron absorption due to a “mucosal block” that is caused by the de-repression of ferritin mRNA translation. Herein, we discuss the physiological function of the IRE/IRP regulatory system.
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影响因子：
29
作者：
Anderson SA;Nizzi CP;Chang YI;Deck KM;Schmidt PJ;Galy B;Damnernsawad A;Broman AT;Kendziorski C;Hentze MW;Fleming MD;Zhang J;Eisenstein RS
通讯作者：
Eisenstein RS
影响因子：
2.1
作者：
Cavill, I
通讯作者：
Cavill, I
影响因子：
3.5
作者：
Cho, Michael H.;Castaldi, Peter J.;Silverman, Edwin K.
通讯作者：
Silverman, Edwin K.
DOI：
10.1016/j.biocel.2004.02.007
发表时间：
2004-11-01
影响因子：
4
作者：
Aisen, P
通讯作者：
Aisen, P
影响因子：
30.8
作者：
Ang, SO;Chen, H;Prchal, JT
通讯作者：
Prchal, JT