Iron-Responsive Elements: Regulatory RNA Sequences That Control mRNA Levels and Translation

Casey, John L.; Hentze, Matthias W.; Koeller, D.M.; Caughman, S. Wright; Rouault, TA; Klausner, R D; Harford, J B

doi:10.1126/science.2452485

Cited by 682 publications

(424 citation statements)

References 26 publications

(11 reference statements)

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“…In healthy tissue, the majority of nonheme iron is stored in the iron storage protein ferritin. Increases in tissue iron levels initiate the production of ferritin (29). Immunocytochemistry-stained sections from the globus pallidus and substantia nigra demonstrate abundant stain for ferritin and its accumulation in glial cells.…”

Section: Discussionmentioning

confidence: 99%

Correlation of R2 with total iron concentration in the brains of rhesus monkeys

Hardy

Gash

Yokel

et al. 2005

Magnetic Resonance Imaging

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Purpose: To estimate the relationship between R 2 ϭ 1/T 2 as measured with a double echo spin echo sequence and total iron concentration in gray matter structures in the brains of aging rhesus monkeys. Materials and Methods:Using a 1.5-T magnetic resonance (MR) imager, we collected double echo spin echo images of the brains of 12 female rhesus monkeys aged between 9 and 23 years. From the double echo images, the transverse relaxation rate R 2 ϭ 1/T 2 was calculated in selected gray matter regions. After the animals were euthanized, their brains were excised and tissue punches were taken of the substantia nigra, globus pallidus, and gray matter regions of the cerebellum. Some of the tissue punches were assayed for total iron using atomic absorption spectroscopy. Results:The range of tissue iron concentration spanned from 15 to 450 g/g wet weight, with the highest levels in the globus pallidus and the lowest levels in the cerebellum. The results show that R 2 was highly correlated with the total iron concentration and that the relationship between R 2 and tissue iron concentration appeared to depend upon the iron concentration. For concentrations above approximately 150 g/g wet weight, R 2 increased with a sensitivity of 0.0484 Ϯ 0.0023 second -1 ( g/g) -1 . In contrast, where the iron concentration was below 150 g/g, R 2 increased at 0.0013 Ϯ 0.0073 second -1 ( g/g) -1 . The bilinear behavior may reflect changes with age in the relative amounts of iron distributed diffusely and in granular form in the globus pallidus and substantia nigra. Histological sections of the tissues stained for iron and ferritin support this hypothesis and indicate that the distribution of ferritin is similar to the distribution of iron. Conclusion:This study reaffirms the value of measuring the MR relaxation rate R 2 for a noninvasive estimate of iron content in the brain and identified limitations in the relationship at low tissue iron concentrations.

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Section: Discussionmentioning

confidence: 99%

Correlation of R2 with total iron concentration in the brains of rhesus monkeys

Hardy

Gash

Yokel

et al. 2005

Magnetic Resonance Imaging

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“…Some excess iron is stored in cells bound to ferritin, an iron storage protein (Wang and Pantopoulos 2011). TfR, ferritin, and ferroportin are controlled by posttranslational regulation of iron status, which involves iron-responsive elements (IREs) (Wang and Pantopoulos 2011;Casey et al 1988). In conjunction with the action of iron-responsive proteins (IRPs), IREs are present in either the 5 0 untranslated regions of ferritin and ferroportin mRNAs or the 3 0 untranslated region of transferrin mRNA blockage or promote translation (Zhang et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Iron deficiency upregulates Egr1 expression

Lee

Prywes

et al. 2015

Genes Nutr

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Iron-deficient anemia is a prevalent disease among humans. We searched for genes regulated by iron deficiency and its regulated mechanism. cDNA microarrays were performed using Hepa1c1c7 cells treated with 100 lM desferrioxamine (DFO), an iron chelator. Early growth response 1 (Egr1) was upregulated with at least 20-fold increase within 4 h and lasted for 24 h, which was confirmed by qRT-PCR. This activation was not seen by ferric ammonium citrate (FAC). DFO increased the transcriptional activity of Egr1-luc (-604 to ?160) and serum response element (SRE)-luc reporters by 2.7-folds. In addition, cycloheximide lowered DFO-induced Egr1 mRNA levels. The upregulation of Egr1 by DFO was accompanied by sustained ERK signals along with phosphorylation of Elk-1. The ERK inhibitor (PD98059) prevented the DFO-induced Egr1 mRNAs. Overexpression of Elk-1 mutant (pElk-1S383A) decreased Egr1 reporter activity. DFO lowered reactive oxygen species (ROS) production and increased caspase 3/7 activity and cell death. DFO-induced iron deficiency upregulates Egr1 in part through transcriptional activation via ERK and Elk-1 signals, which may be important in the regulation of cell death in hepatoma cells. Our study demonstrated that iron depletion controlled the expression of Egr1, which might contribute to decisions about cellular fate in response to iron deficiency.

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Section: Introductionmentioning

confidence: 99%

“…TfR1 expression is ubiquitous, consistent with its role in cellular iron delivery. The stability of TfR1 mRNA is negatively regulated by intracellular iron levels through iron-responsive elements (IREs) in the 3Ј untranslated region (Mattia et al, 1984;Ward et al, 1984;Rao et al, 1985;Sciot et al, 1987;Owen and Kuhn, 1987;Casey et al, 1988;Mullner and Kuhn, 1988;Lu et al, 1989;Mullner et al, 1989).TfR2 differs from TfR1 in notable ways. TfR2 binds Tf in a pH-dependent manner, but its affinity for Fe 2 Tf (K D ϳ30 nM; Kawabata et al, 2000;West et al, 2000) is significantly lower than that of TfR1 (K D ϳ1 nM, Tsunoo and Sussman, 1983;Enns et al, 1991;Richardson and Ponka, 1997).…”

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confidence: 99%

Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway

Johnson

Chen

Murchison

et al. 2007

MBoC

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Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1), the protein that delivers iron to cells through receptor-mediated endocytosis of diferric transferrin (Fe 2 Tf). TfR2 also binds Fe 2 Tf, but it seems to function primarily in the regulation of systemic iron homeostasis. In contrast to TfR1, the trafficking of TfR2 within the cell has not been extensively characterized. Previously, we showed that Fe 2 Tf increases TfR2 stability, suggesting that trafficking of TfR2 may be regulated by interaction with its ligand. In the present study, therefore, we sought to identify the mode of TfR2 degradation, to characterize TfR2 trafficking, and to determine how Fe 2 Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe 2 Tf increases the fraction of TfR2 localizing to recycling endosomes and decreases the fraction of TfR2 localizing to late endosomes. Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to Fe 2 Tf, increases the rate of receptor turnover and prevents stabilization by Fe 2 Tf, indicating a direct role of Fe 2 Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif. INTRODUCTIONA truncation mutant of transferrin receptor 2 (TfR2), TfR2/ Y250X, causes a rare form of hereditary hemochromatosis (type 3, HFE3), an iron overload disorder characterized by excess absorption of dietary iron and consequent deposition of iron in liver and other parenchymal tissues (Camaschella et al., 1999(Camaschella et al., , 2000. The analogous mutation or knockout of Trfr2 in mice reproduces the disease phenotype (Fleming et al., 2002;Wallace et al., 2005). Thus, TfR2 is required for normal iron homeostasis.TfR2, cloned in 1999, is a homologue of transferrin receptor 1 (TfR1; Kawabata et al., 1999). The extracellular domains of the two receptors are 45% identical and 67% similar. TfR1 functions to deliver iron to cells through receptor-mediated endocytosis of its ligand transferrin (Tf), a serum protein that transports iron (Dautry-Varsat et al., 1983;Klausner et al., 1983). On the cell surface, TfR1 binds iron-saturated transferrin (Fe 2 Tf) at slightly basic pH. Fe 2 Tf-TfR1 then internalizes in clathrin-coated vesicles to early endosomes.In the acidic pH of early endosomes, iron releases from Tf, whereas Tf remains bound to TfR1. The complex then recycles, from either early or recycling endosomes, to the cell surface. At the slightly basic pH of the cell surface, TfR1 releases unsaturated Tf (apoTf) and again binds Fe 2 Tf. TfR1 expression is ubiquitous, consistent with its role in cellular iron delivery. The stability of TfR1 mRNA is negatively regulated by intracellular iron levels through iron-responsive elements (IREs) in the 3Ј untranslated region (Mattia et al., 1984;Ward et al., 1984;Rao et al., 1985;Sciot et al., 1987;Owen and Kuhn, 19...

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Iron-Responsive Elements: Regulatory RNA Sequences That Control mRNA Levels and Translation

Cited by 682 publications

References 26 publications

Correlation of R2 with total iron concentration in the brains of rhesus monkeys

Correlation of R2 with total iron concentration in the brains of rhesus monkeys

Iron deficiency upregulates Egr1 expression

Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway

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