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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human transferrin mRNA contains a 5'-untranslated region that (1) has homology to an iron responsive element and (2) is implicated in translational iron regulation of human transferrin transgenes in transgenic mice. Ferritin mRNA contains a 5'-untranslated region iron-responsive element, but iron regulation of ferritin differs from that of human transferrin transgenes in both magnitude and direction. Structural differences between the ferritin iron-responsive element and the human transferrin putative iron-responsive element may influence their iron-regulatory protein interactions and direct the differing translational responses. This study examines human transferrin RNA nucleotide sequence requirements for binding of cytoplasmic proteins and purified iron-regulatory protein. Mutations of the putative transferrin iron-responsive element similarly affected binding of purified iron-regulatory protein and liver cytoplasmic proteins, providing evidence that the IRP is one of the liver cytoplasmic proteins that binds the human transferrin iron-regulatory element and suggesting that it may be involved in iron-regulation of transferrin.
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PMID:The 5'-untranslated region of human transferrin mRNA, which contains a putative iron-regulatory element, is bound by purified iron-regulatory protein in a sequence-specific manner. 762 32

Replenishment of ascorbate in cultured cells, which are almost uniformly vitamin-deficient, increases ferritin mRNA translation in response to iron by 20-fold (Toth, I., Rogers, J. T., McPhee, J. A., Elliott, S. M., Abramson, S. L., and Bridges, K. R. (1995) J. Biol. Chem. 270, 2846-2852). We now demonstrate that ascorbate increases cytosolic aconitase activity. The iron-responsive element-binding protein (IRP-1) exists in three states: bound to mRNA without aconitase activity, free in the cytosol without aconitase activity, and free in the cytosol with aconitase activity. Ascorbate converts free IRP-1 to the enzymatically active form. Enhanced ferritin synthesis with subsequent iron stimulation is due to the altered equilibrium of the free IRP-1. The cellular biology of iron is closely intertwined with that of ascorbate.
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PMID:Ascorbic acid enhances ferritin mRNA translation by an IRP/aconitase switch. 764 38

Ferritin and transferrin receptors are co-ordinately regulated by the same RNA-protein interaction: the conserved iron regulatory element (IRE) in mRNA and the IRE-binding protein (IRE-BP/IRP/FRP/P-90). The 28 nucleotide IRE in ferritin mRNA is a single copy, with base-paired flanking regions (FL), located near the 5' cap. In the transferrin receptor mRNA, the IRE is located in the 3' untranslated region, as five variable copies and lacking predicted base-paired flanking regions; an alternate predicted structure without IREs has similar stability. When iron is scarce, ferritin mRNA does not form polyribosomes whereas the transferrin receptor mRNA is translated; when iron is abundant, ferritin mRNA forms polyribosomes and the transferrin receptor mRNA is degraded. To investigate structures which contribute to differences in the regulation of the two mRNAs, the effect of mutation of the ferritin FL was studied. Changes in structure (changes in reactivity with RNase V1 and RNase S1. Fe-bleomycin) and changes in function (translation in rabbit reticulocyte extracts) were compared for mutant and wild-type FL sequences in ferritin mRNA. The disruption of a triplet of base-pairs in the FL had diminished regulation; a second mutation to restore the triplet base-pairs conferred wild-type translational regulation. Conformation of the mutant RNA-IRE-BP complex was also different. We show that the triplet of base-pairs is conserved; the triplet is also the location of IRE-BP-dependent conformational changes in the FL structure previously observed. Increasing FL base-pairs had no effect on function. Structural changes associated with altered function included bleomycin sites in the IRE, suggesting an alternate conformation of the hairpin, and different base-stacking (V1 sensitivity) in the FL. The function of the FL, which is altered by mutation of phylogenetically conserved triplet base-pairs, may be enhancement of formation of a particular IRE stem-loop-protein interaction.
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PMID:The influence of the base-paired flanking region on structure and function of the ferritin mRNA iron regulatory element. 768 92

Noncoding sequences regulate mRNA and DNA function. IREs are a highly conserved family of noncoding mRNA sequences which coordinate ferritin mRNA translation and transferrin receptor mRNA stability by interactions with specific negative regulator protein, the IRP. RNA interactions with the IRP are modulated by cellular iron. The protein IRP binds to the entire IRE causing conformational changes in flanking region [Harrell et al. (1991) PNAS 88:4166-4170). The IRE+FL is the first RNA element encoding both positive and negative translational control and serves as a model mRNA regulatory elements. Folding of the IREs indicated previously by reactivity with chemical and enzymatic probes [E.C Theil (1994) Biochem. J., 304:1-11) is confirmed by using 1H, 15N and 31P (1) NMR) and CD to show that IRE secondary structure [hairpin-hexaloop (HL)/stem/internal loop or bulges] is folded, CD spectra display Mg2+ dependent structural changes in the temperature range used in the studies of IRE function. G/A substitution was shown by NMR and UV-vis to decrease stability of the folded IRE [H.Sierzputowska-Gracz et al. (1995) Nucl. Acids Res. 23:146-153]. A hairpin loop mutation affected only negative translational control.
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PMID:15N NMR and CD studies of the IRE (iron regulatory element in ferritin mRNA with single base substitution in the hairpin loop. 864 70

Macrophage effector functions are influenced by their iron status and by shifts in the balance between type 1 Th1 and Th2 cells. To elucidate the influence of the Th2 cytokines IL-4 and IL-13 on macrophage iron metabolism, we investigated activated primary mouse macrophages and the murine macrophage cell line J774. Stimulation of J774 cells and primary macrophages with IFN-gamma/LPS activates the RNA binding affinities of iron regulatory protein-1 (IRP-1) and IRP-2 for iron-responsive elements, leading to translational repression of the iron storage protein ferritin. Activation of IRP-1 and IRP-2 is caused by increased formation of nitric oxide (NO) via stimulation of the inducible NO synthase by IFN-gamma/LPS. Treatment of macrophages with IL-4 and/or IL-13 before stimulation with IFN-gamma/LPS suppresses NO formation and IRP activation, with concomitantly enhanced ferritin synthesis despite a small reduction in ferritin heavy chain mRNA levels. The mRNA levels for the membrane receptor for iron uptake, transferrin receptor (TfR), decrease following stimulation with IFN-gamma/LPS, although IRP-mediated stabilization of the TfR mRNA would have been expected. This as yet unidentified proximal inhibitory signal by IFN-gamma/LPS is antagonized by IL-4 and/or IL-13, which leads to increased TfR mRNA expression in an IRP-independent manner. Thus, IL-4 and IL-13 regulate the iron metabolism of activated macrophages by at least two different pathways: first, by opposing NO-mediated IRP activation, thereby increasing ferritin translation; and second, by an IRP-independent augmentation of TfR mRNA expression. We suggest that IL-4 and IL-13 may enhance iron uptake and storage in activated macrophages and thereby contribute to down-regulation of macrophage effector functions.
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PMID:Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13. 897 18

Iron regulatory protein 1 (IRP1) and IRP2 are cytoplasmic RNA binding proteins that coordinate cellular iron homeostasis in mammals. We investigated the effect of dietary iron intake on rat liver IRP activity in relation to the abundance of two targets of IRP action, ferritin and mitochondrial aconitase (m-aconitase). Rats were fed diets containing 2, 11, 20, 37 (control), 72 or 107 mg iron/kg diet for 3 wk. RNA binding activity of IRP1 and IRP2 was enhanced one- to twofold in rats fed 11 or 2 mg iron/kg diet compared with control rats. IRP RNA binding activity was inversely correlated to blood hemoglobin levels (r = -0.787; P < 0.0001). Compared with control rats, liver ferritin levels were depressed in rats fed 20 mg iron/kg diet and were undetectable in rats ingesting diets with 11 or 2 mg iron/kg diet. Ferritin concentrations were biphasically related to IRP RNA binding activity with the regulation of IRP occurring before the onset of ferritin accumulation. Iron deficiency caused up to a 50% decline in m-aconitase abundance. IRP RNA binding activity and m-aconitase abundance were inversely correlated (r = -0.751; P < 0.0001). Our results indicate that (1) liver IRP activity is responsive to a range of dietary iron levels, (2) there appears to be a differential effect of IRPs on ferritin and m-aconitase abundance, and (3) activation of IRPs may contribute to the alterations in energy metabolism in iron deficiency through an impairment of m-aconitase synthesis.
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PMID:Dietary iron intake modulates the activity of iron regulatory proteins and the abundance of ferritin and mitochondrial aconitase in rat liver. 903 23

The mechanism of drug resistance to gallium nitrate is not known. Since gallium can be incorporated into ferritin, an iron storage protein that protects cells from iron toxicity, we investigated whether ferritin expression was altered in gallium-resistant (R) CCRF-CEM cells. We found that the ferritin content of R cells was decreased, while heavy chain ferritin mRNA levels and iron regulatory protein-1 (IRP-1) RNA binding activity were increased. IRP-1 protein levels were similar in gallium-sensitive (S) and R cells, indicating that R cells contain a greater proportion of IRP-1 in a high affinity mRNA binding state. 59Fe uptake and transferrin receptor expression were decreased in R cells. In both S and R cells, gallium inhibited cellular 59Fe uptake, increased ferritin mRNA and protein, and decreased IRP-1 binding activity. Gallium uptake by R cells was markedly diminished; however, the sensitivity of R cells to gallium could be restored by increasing their uptake of gallium with excess transferrin. Our results suggest that R cells have developed resistance to gallium by down-regulating their uptake of gallium. In parallel, iron uptake by R cells is also decreased, leading to changes in iron homeostasis. Furthermore, since gallium has divergent effects on iron uptake and ferritin synthesis, its action may also include a direct effect on ferritin mRNA induction and IRP-1 activity.
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PMID:Resistance to the antitumor agent gallium nitrate in human leukemic cells is associated with decreased gallium/iron uptake, increased activity of iron regulatory protein-1, and decreased ferritin production. 911 86

In vertebrates, body Fe homeostasis is maintained through the regulation of its intestinal absorption. In addition, because Fe is both essential and toxic, intracellular Fe levels are tightly regulated. Consequently, intestinal epithelial cells are in the unique position of being responsible simultaneously for the regulation of body Fe absorption and the regulation of their intracellular Fe levels to remain viable. We tested the hypothesis that the regulation of transepithelial Fe transport and the regulation of intracellular Fe levels are sensitive to a common effector. To this end, we used a recently developed protocol to obtain cultured intestinal epithelial cells with defined intracellular Fe concentrations. In these cells we tested Fe absorption and Fe regulatory protein (IRP) activities. We found that transepithelial Fe transport was inversely related to 20-200 microM intracellular Fe and that Caco-2 cells expressed Fe regulatory protein-1 and Fe regulatory protein-2 activities. Fe regulatory protein-1 activity, Fe regulatory protein-2 mass, transferrin receptor density, and ferritin levels were regulated by intracellular Fe in the same range (20-200 microM) that affected transepithelial Fe transport. These results suggest that a common Fe-responsive factor regulates both intracellular Fe levels and Fe absorption by Caco-2 cells.
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PMID:Intracellular iron regulates iron absorption and IRP activity in intestinal epithelial (Caco-2) cells. 927 4

The regulation of transferrin-receptor synthesis was studied in J2E erythroid cells induced to differentiate with erythropoietin. Nuclear run-on assays demonstrated that transcription of the transferrin-receptor gene rose markedly after erythropoietin treatment. In addition, transferrin-receptor mRNA was stabilised and this was associated with an increase in the activity of the RNA-binding protein IRP (iron regulatory protein). As a result of increased transcription and mRNA stabilisation, steady-state RNA levels increased 10-20-fold. However, despite these large increases in mRNA, translation only doubled; consequently, modest increases in total protein and surface transferrin receptors were observed. Moreover, this rise in transferrin receptors was transient, and correlated with a burst of proliferation shortly after erythropoietin treatment. The expected inverse relationship between transferrin receptors and ferritin did not occur during J2E maturation as translation of both ferritin subunits increased when transferrin-receptor mRNA levels rose. Analysis of mutant J2E clones incapable of synthesising haemoglobin revealed that surface transferrin-receptor levels were only 15-25% that of the parental erythroid line. We propose that the surface expression of transferrin receptors in J2E cells is governed by three factors: basal levels essential for normal growth in culture; elevated levels needed for haemoglobin synthesis; and a transient erythropoietin-induced increase that is required for the final burst of proliferation. It was concluded that the regulation of transferrin-receptor production in erythropoietin-stimulated J2E cells is complex and that there are several sites of control.
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PMID:Complex regulation of transferrin receptors during erythropoietin-induced differentiation of J2E erythroid cells--elevated transcription and mRNA stabilisation produce only a modest rise in protein content. 936 56

Control of cellular iron homoeostasis is performed by iron regulatory protein 1 (IRP1) through post-transcriptional modifications. This protein is sensitive to intracellular iron availability, being activated at low iron levels and inactivated at high iron levels, conditions that signal the increased expression of the transferrin receptor or of ferritin respectively. IRP1 is known to be activated by some oxidants such as H2O2 and NO. delta-Aminolaevulinic acid (ALA), previously found to produce reactive oxygen species and a carbon-centred radical, to release iron from ferritin, and to increase rat liver and brain non-haem iron and ferritin, was investigated for its effects on IRP1 activity in cultured hamster pulmonary fibroblasts. We have found that 1-2 mM ALA produced a 2-3-fold activation of IRP. On incubation with 1-4 mM succinylacetone methyl ester, a potent ALA dehydratase inhibitor, a 3-4-fold activation of the protein was observed, accompanied by a 40% increase in the intracellular ALA concentration. When cells were incubated in the presence of ALA or succinylacetone methyl ester, N-acetylcysteine inhibited IRP1 activation, suggesting that the observed effect is mediated by an oxidative process. We surmise that ALA-induced IRP1 activation might act as a co-sensor of iron homoeostasis.
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PMID:Haem precursor delta-aminolaevulinic acid induces activation of the cytosolic iron regulatory protein 1. 939 27


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