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

Excess iron results in an increase in the translation of ferritin mRNA and a decrease in the stability of transferrin receptor (TfR) mRNA. These coordinate regulatory events are mediated by similar sequence/structure motifs that exist within the 5' untranslated region (5'UTR) of the ferritin mRNA and the 3'UTR of the TfR mRNA. We have referred to these motifs as iron-responsive elements (IREs). The IREs from both transcripts interact with a cytoplasmic protein that we have called the IRE-binding protein (IRE-BP). The activity but not the amount of the IRE-BP is dependent on the cellular iron status. The biochemical basis for the altered activity of the IRE-BP appears to be the reversible oxidation-reduction of one or more cysteines in the IRE-BP. The IRE-BP is a 90- to 95-kD cytosolic protein that has been purified to homogeneity by RNA affinity chromatography, and the cDNA corresponding to the IRE-BP has been molecularly cloned. Collectively, our data support a model in which the interaction between the IRE-BP and the ferritin IRE results in attenuation of translation, and similar interaction with TfR mRNA can protect the transcript from rapid degradation mediated by a rapid turnover determinant within the 3'UTR.
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PMID:Coordinate post-transcriptional regulation of ferritin and transferrin receptor expression: the role of regulated RNA-protein interaction. 213 55

Changes in transcription/accumulation of ferritin mRNA accompany cell differentiation and development as cells establish the pattern of iron storage and metabolism that matches their specialized features. Signals which induce changes in ferritin gene expression include hormones (thyrotropin in thyroid cells), monokines (tumor necrosis factor alpha in myoblasts, and preadipocytes), phagocytosis and/or inducing agents (erythrophagocytosis in macrophages, phorbol esters in promyelocytes, and dimethyslulfoxide in proerythroblasts), heat shock (in red cells) and light (in leaf mesophyll). Iron, which has a major effect on the translation of ferritin mRNA, also leads to synthesis and/or accumulation of ferritin mRNA in hepatocytes, adult red cells, HeLa cells, and undifferentiated plant cells. Iron-induced changes in ferritin mRNA composition allow cells to synthesize large amounts of different ferritins in response to excess iron. Whether iron will act both on translation and transcription may relate to the uses of stored iron by the cell (iron reserve for other cells? detoxification?) and the magnitude of the iron signal relative to the existing pool of ferritin mRNA. Translational regulation of ferritin mRNA depends on two distinctive features of the RNA: (1) conserved regulatory sequence of 28 nucleotides occurs in the 5' noncoding region (iron 'regulatory' or 'responsive' element, IRE) which interacts with cytoplasmic regulator proteins, present in animal cells, that block initiation; sequences in the 3' untranslated region can modulate translation when the IRE is present. (2) Ferritin mRNA, either deregulated by iron induction in cells or isolated from cells (polyA+), forms initiation complexes efficiently compared to other cellular mRNAs. The structure of the IRE, which is also found in the 3' untranslated region of the iron-destabilized transferrin receptor mRNA, has begun to be analyzed by computer prediction, site-directed mutagenesis, and solution behavior. The results to date show that the IRE is a hairpin with bulges and loops that is stacked upon a base-paired flanking region (FL) with varying sequence. Interactions of the IRE+FL with other parts of ferritin mRNA are indicated by comparing the reactivity of natural ferritin mRNA with an oligomer (n = 55). The structure of the stem nearest the hairpin loop is sequence-dependent and flexible. Variations in the distance of the IRE from the cap in various ferritin mRNAs, compensated by the length of FL, and the structural properties of the IRE+FL suggest that the 5' regulatory structure of ferritin mRNA includes the IRE+FL.
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PMID:Ferritin mRNA translation, structure, and gene transcription during development of animals and plants. 213 59

Iron regulates the synthesis of two proteins critical for iron metabolism, ferritin and the transferrin receptor, through novel mRNA/protein interactions. The mRNA regulatory sequence (iron-responsive element (IRE)) occurs in the 5'-untranslated region of all ferritin mRNAs and is repeated as five variations in the 3'-untranslated region of transferrin receptor mRNA. When iron is in excess, ferritin synthesis and iron storage increase. At the same time, transferrin receptor synthesis and iron uptake decrease. Location of the common IRE regulatory sequence in different noncoding regions of the two mRNAs may explain how iron can have opposite metabolic effects; when the IRE is in the 5'-untranslated region of ferritin mRNA, translation is enhanced by excess iron whereas the presence of the IREs in the 3'-untranslated region of the transferrin receptor mRNA leads to iron-dependent degradation. How and where iron actually acts is not yet known. A soluble 90-kDa regulatory protein which has been recently purified to homogeneity from liver and red cells specifically blocks translation of ferritin mRNA and binds IRE sequences but does not appear to be an iron-binding protein. The protein is the first specific eukaryotic mRNA regulator identified and confirms predictions 20 years old. Concerted regulation by iron of ferritin and transferrin receptor mRNAs may also define a more general strategy for using common mRNA sequences to coordinate the synthesis of metabolically related proteins.
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PMID:Regulation of ferritin and transferrin receptor mRNAs. 215 53

A post-transcriptional regulatory protein, termed iron regulatory factor (IRF), that binds specifically to the iron-responsive elements of ferritin and transferrin receptor mRNA, has recently been identified in the cytoplasm of human and mouse cells. Activation of this factor by low intracellular iron levels leads to inhibition of ferritin translation and an increase of TR mRNA stability. To investigate whether these feedback regulatory mechanisms are conserved during evolution, we analysed cytoplasmic extracts from 12 different species for a specific IRE-binding activity. We found mRNA-binding proteins in chicken, frog, fish and fly, which are equivalent to human and mouse IRF in gel-retardation assays with radiolabeled RNA transcripts. Competition experiments, molecular weight determinations, and modulation of the mRNA-binding activity in response to intracellular iron levels or reduction by beta-mercaptoethanol indicate that IRF has similar structural and functional properties in these different species.
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PMID:The mRNA-binding protein which controls ferritin and transferrin receptor expression is conserved during evolution. 215 91

Iron-responsive elements (IREs) are stemloop structures found in the mRNAs encoding ferritin and the transferrin receptor. These elements participate in the iron-induced regulation of the translation of ferritin and the stability of the transferrin receptor mRNA. Regulation in both instances is mediated by binding of a cytosolic protein to the IREs. High-affinity binding is seen when cells are starved of iron and results in repression of ferritin translation and inhibition of transferrin receptor mRNA degradation. The IRE-binding protein (IRE-BP) has been identified as an approximately 90-kDa protein that has been purified by both affinity and conventional chromatography. In this report we use RNA affinity chromatography and two-dimensional gel electrophoresis to isolate the IRE-BP for protein sequencing. A degenerate oligonucleotide probe derived from a single peptide sequence was used to isolate a cDNA clone that encodes a protein containing 13 other sequenced peptides obtained from the IRE-BP. Consistent with previous characterization of the IRE-BP, the cDNA encodes a protein of 87 kDa with a slightly acidic pI, and the corresponding mRNA of approximately 3.6 kilobases is found in a variety of cell types. The encoded protein contains a nucleotide-binding consensus sequence and regions of cysteine and histidine clusters. This mRNA is encoded by a single gene on human chromosome 9, a finding consistent with previous localization by functional mapping. The protein contains no previously defined consensus motifs for either RNA or DNA binding. The simultaneous cloning of a different, but highly homologous, cDNA suggests that the IRE-BP is a member of a distinct gene family.
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PMID:Cloning of the cDNA encoding an RNA regulatory protein--the human iron-responsive element-binding protein. 217 68

In genetic hemochromatosis, metabolic studies have demonstrated inappropriately increased iron absorption by cells of the duodenal mucosa. It is not clear whether this reflects an intrinsic abnormality of iron homeostasis at this site or is a consequence of a more generalized defect in cellular iron metabolism particularly involving the liver. We have previously used the expression of iron-related proteins as markers of iron homeostasis and have demonstrated normal regulation of the transferrin receptor and ferritin in the liver in this condition. In the present study we used immunohistochemical techniques to study transferrin-receptor expression in the gastrointestinal epithelium in normal subjects and patients with iron overload. In untreated genetic hemochromatosis and normal subjects, villus epithelial cells expressed receptor in the basolateral, subnuclear region. In contrast, in patients with secondary iron overload, receptor staining was absent in villus epithelial cells. The cells in the duodenal crypts showed intense staining for the transferrin receptor in all subjects investigated, a finding consistent with the known behavior of this receptor in proliferating cells. Given that body iron stores in both types of iron overload were comparable, these findings indicating a failure of down-regulation of the villus enterocyte transferrin receptor in genetic hemochromatosis may reflect the presence of a regulatory defect associated with the inability to control iron absorption in this condition.
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PMID:Differential expression of transferrin receptor in duodenal mucosa in iron overload. Evidence for a site-specific defect in genetic hemochromatosis. 217 37

Recent studies indicate that serum transferrin receptor levels are a quantitative index of tissue receptor mass. To determine whether the latter plays a role in the regulation of iron absorption, we examined the relationship between serum receptor, serum ferritin and iron absorption in healthy subjects. Using radioisotopic techniques we measured absorption of inorganic iron in 174 subjects and dietary nonhaem iron in 60 subjects. With both forms of iron, the correlation with absorption was far lower for serum receptor than for serum ferritin and was no longer significant when subjects with depleted iron stores were excluded. These results indicate that in normal subjects the iron store is the main physiological determinant of iron absorption and that in the absence of iron deficiency, tissue receptor mass, reflected by serum transferrin receptor levels, has no discernible influence.
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PMID:Serum transferrin receptor as an index of iron absorption. 220 11

Transferrin receptors were characterized with 125I-ferrotransferrin on membrane fractions prepared from the rodent forebrain. The distribution of transferrin receptors in the rat brain was investigated further by in vitro autoradiography. Saturation binding analysis revealed an apparent single class of sites with a dissociation constant of 2 nM and a binding site density of 15 pmol/g. The Hill coefficient derived from these data was 1.05, indicating the absence of cooperativity and that 125I-ferrotransferrin binds to a single class of sites. Estimates of the kinetically determined KD for forebrain membranes were within the 2-4 nM range, in agreement with the equilibrium measurements. Apotransferrin and ferrotransferrin competitively displaced the binding of 125I-ferrotransferrin, while ferritin, albumin, and cytochrome c failed to compete for the binding site. Ceruloplasmin, the copper transport protein, was a weak inhibitor of 125I-ferrotransferrin binding. Autoradiographic localization studies demonstrate a heterogeneous distribution of transferrin receptors in the rat brain. Transferrin receptor densities were markedly elevated over the cerebral cortex and the hippocampus. Moderate to high 125I-ferrotransferrin binding was also apparent throughout areas involved in motor functions, including the caudate-putamen, the nucleus accumbens, the substantia nigra, the red nucleus, and the cerebellum.
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PMID:Characterization and distribution of transferrin receptors in the rat brain. 223 Aug 4

Ferritin messenger RNA has been shown to be translationally inactivated by the binding of a cytosolic protein to a 28-nucleotide iron-responsive element (IRE) located in the 5'-untranslated region of the mRNA. This interaction has been studied using quantitative receptor-ligand binding methods with gel retardation and nitrocellulose filter binding assays for the separation of bound complex from free RNA. In competition assays the entire 5'-untranslated region and the isolated IRE bound identically. The specificity of the RNA binding was studied using IRE variants. Two IREs from transferrin receptor mRNA and several variants with single base substitutions in the stem or loop had similar affinities. RNAs which could not form a stem-loop structure bound 1000-fold less well. These studies demonstrate the importance of the RNA conformation and the relative insensitivity of binding to much of the primary sequence. Saturation assays with increasing concentrations of 32P-IRE resulted in a binding hyperbola characteristic of mass action binding to a single class of sites with a KD = 0.09 nM. At 37 degrees C the dissociation rate is 0.04 min-1 (t 1/2 = 17 min). This rate is fast enough to account for the shift of ferritin RNA from the ribonucleoprotein pool to polysomes after rats are injected with iron. Determination of the concentration of the repressor requires accounting for three interconverting pools: free active repressor, mRNA-bound protein, and inactive (low affinity) repressor. Rat liver cytosol has a concentration of free active repressor of about 1 pmol/mg protein. Protein bound to endogenous mRNA can be measured by pretreatment with micrococcal nuclease or by separation with DEAE-Sepharose chromatography; it is present at a level similar to that of the free active protein. Inclusion of high levels of thiol reductants in the binding incubations reduces the inactive or low affinity repressor, forming unstably activated protein which has the same KD as the endogenous active protein; this inactive or low affinity protein is 2-4 times more abundant. A mechanism for iron regulation is proposed which accounts for the kinetics, the multiple protein pools, and the characteristics of the protein in these pools.
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PMID:Determinants of the interaction between the iron-responsive element-binding protein and its binding site in rat L-ferritin mRNA. 232 9

The ferritin concentration in peripheral blood lymphocyte extracts was measured in 10 normal subjects, 7 patients with homozygous beta-thalassaemia, and 5 patients with iron-deficiency anaemia. The mean intracellular ferritin content was found increased in beta-thalassaemia and reduced in iron-deficient patients. Incubation of mononuclear cells in phytohaemagglutinin medium led to an increase of DNA synthesis concomitant with an increased number of lymphocytes bearing transferrin receptor and interleukin-2 receptor as measured by immunofluorescent technique. Although there was an immunological impairment of lymphocytes in patients with either iron depletion or iron loading compared to normal subjects, their ability to express transferrin receptor and interleukin-2 receptor on their cell surface was normal.
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PMID:Expression of cell-surface transferrin receptor following in vitro stimulation of peripheral blood lymphocytes in patients with beta-thalassaemia and iron-deficiency anaemia. 232 91


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