UNIPROT:P02794 - FACTA Search

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

A Triton X-100 solubilized macromolecular complex of transferrin and a membrane constituent can be isolated by gel chromatography from rabbit reticulocytes previously incubated with 125I-labeled transferrin. The apparent molecular weight of this complex is close to that of ferritin, or about 445 000. On sodium dodecyl sulfate gel electrophoresis the complex displays two glycoprotein subunits, of molecular weights 176 000 and 95 000 in addition to transferrin. A transferrin-binding fraction with a molecular weight near 400 000, containing these subunits, can also be identified in membranes of nonincubated reticulocytes. The corresponding membrane fraction from mature erythrocytes, which have lost transferrin-binding activity, displays both protein subunits, but the 176 000 molecular weight component fails to give a PAS stain for carbohydrate. Treatment of reticulocytes with Pronase, which destroys the ability of the cells to form specific complexes with transferrin, degrades both components. We believe these results are consistent with the hypothesis that the primary transferrin receptor of the rabbit reticulocyte is a glycoprotein of molecular weight in the range 350 000-400 000, comprised of a combination of two subunits with molecular weights 176 000 and 95 000, respectively. Transferrin-binding activity appears to depend on the carbohydrate moiety of the 176 000 subunit.
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PMID:Transferrin receptor of the rabbit reticulocyte. 84 17

The translation of ferritin mRNA and degradation of transferrin receptor mRNA are regulated by the interaction of an RNA-binding protein, the iron-responsive element binding protein (IRE-BP), with RNA stem-loop structures known as iron-responsive elements (IREs) contained within these transcripts. IRE-BP produced in iron-replete cells has aconitase (EC 4.2.1.3) activity. The protein shows extensive sequence homology with mitochondrial aconitase, and sequences of peptides prepared from cytosolic aconitase are identical with peptides of IRE-BP. As an active aconitase, IRE-BP is expected to have an Fe-S cluster, in analogy to other aconitases. This Fe-S cluster has been implicated as the region of the protein that senses intracellular iron levels and accordingly modifies the ability of the IRE-BP to interact with IREs. Expression of the IRE-BP in cultured cells has revealed that the IRE-BP functions either as an active aconitase, when the cells are iron-replete, or as an active RNA-binding protein, when the cells are iron-depleted. We compare properties of purified authentic cytosolic aconitase from beef liver with those of IRE-BP from tissue culture cells and establish that characteristics of the physiologically relevant form of the protein from iron-depleted cells resemble those of cytosolic aconitase apoprotein. We demonstrate that loss of the labile fourth iron atom of the Fe-S cluster results in loss of aconitase activity, but that more extensive cluster alteration is required before the IRE-BP acquires the capacity to bind RNA with the affinity seen in vivo. These results are consistent with a model in which the cubane Fe-S cluster is disassembled when intracellular iron is depleted.
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PMID:Cellular regulation of the iron-responsive element binding protein: disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding. 128 44

In recent reports attention has been drawn to the extensive amino acid homology between pig heart, yeast, and Escherichia coli aconitases (EC 4.2.1.3) and the iron-responsive element binding protein (IRE-BP) of mammalian cells [Rouault, T. A., Stout, C. D., Kaptain, S., Harford, J. B. & Klausner, R. D. (1991) Cell 64, 881-883.; Hentze, M. W. & Argos, P. (1991) Nucleic Acids Res. 19, 1739-1740.; Prodromou, C., Artymiuk, P. J. & Guest, J. R. (1992) Eur. J. Biochem. 204, 599-609]. Iron-responsive elements (IREs) are stem-loop structures located in the untranslated regions of mRNAs. IRE-BP is required in the posttranscriptional regulation of ferritin mRNA translation and stabilization of transferrin receptor mRNA. In spite of substantial homology between the amino acid sequences of mammalian mitochondrial aconitase and IRE-BP, the mitochondrial protein does not bind IREs. However, there is a second aconitase, found only in the cytosol of mammalian tissues, that might serve as an IRE-BP. To test this possibility, we have prepared sufficient quantities of the heretofore poorly characterized beef liver cytosolic aconitase. This enzyme is isolated largely in its active [4Fe-4S] form and has a turnover number similar to that of mitochondrial aconitase. The EPR spectra of the two enzymes are markedly different. The amino acid composition, molecular weight, isoelectric point, and the sequences of six random peptides clearly show that these physicochemical and structural characteristics are identical to those of IRE-BP, and that c-aconitase is distinctly different from m-aconitase. In addition, both cytosolic aconitase and IRE-BP can have aconitase activity or function as IRE-BPs, as shown in the following paper and elsewhere [Zheng, L. Kennedy, M. C., Blondin, G. A., Beinert, H. & Zalkin, H. (1992) Arch. Biochem. Biophys., in press]. This leads us to the conclusion that cytosolic aconitase is IRE-BP.
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PMID:Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein. 133 46

Sixty full-term gravidas were divided into four groups, normal insidious iron deficiency, mild iron deficient anemia and moderate iron deficient anemia, according to their iron nutritional state determined by the measurement of hematologic and iron biochemical indexes. The iron nutritional state of newborns in each group and the level and the affinity of transferrin receptor in placenta were also studied. The iron nutritional state of newborns was found to decrease mildly along with the decrease of their mothers' iron nutritional state, especially the decrease of serum ferritin, but the differences were not statistically significant. It was suggested that the iron nutritional state of newborns was relatively normal although their mothers were in severe iron deficiency. The differences of transferrin receptor levels were significant among the four groups, the mild IDA group had the highest level of transferrin receptor, which was 1.68 times of normal group and 1.77 times of moderate IDA group. The differences between each two groups were significant. The differences of dissociate constant (Kd) of transferrin receptor were not significant among the four groups, indicating that the iron metabolism between mothers and their babies was regulated not by changing the affinity of transferrin binding to its receptor but by changing the numbers of transferrin receptor to maintain the relative stableness of newborns iron nutritional state.
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PMID:[Effect of placental transferrin receptors on iron nutritional state of normal full-term gravidas and their newborns]. 133 10

Post-transcriptional regulation of genes important in iron metabolism, ferritin and the transferrin receptor (TfR), is achieved through regulated binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP), to RNA stem-loop motifs known as iron-responsive elements (IREs). Binding of the IRE-BP represses ferritin translation and represses degradation of the TfR mRNA. The IRE-BP senses iron levels and accordingly modifies binding to IREs through a novel sensing mechanism. An iron-sulfur cluster of the IRE-BP reversibly binds iron; when cytosolic iron levels are depleted, the cluster becomes depleted of iron and the IRE-BP acquires the capacity to bind IREs. When cytosolic iron levels are replete, the IRE-BP loses RNA binding capacity, but acquires enzymatic activity as a functional aconitase. RNA binding and aconitase activity are mutually exclusive activities of the IRE-BP, and the state of the iron-sulfur cluster determines how the IRE-BP will function.
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PMID:An iron-sulfur cluster plays a novel regulatory role in the iron-responsive element binding protein. 142 65

Maintenance of cellular iron homeostasis demands the coordination of iron uptake, intracellular storage, and utilization. Recent investigations suggest that a single genetic regulatory system orchestrates the expression of proteins with central importance for all three aspects of cellular iron metabolism at the level of mRNA stability and translation. Two components of this regulatory system have been defined: a cis-acting mRNA sequence/structure motif called "iron-responsive element" (IRE) and a specific trans-acting cytoplasmic binding protein, here referred to as "IRE-binding protein" (IRE-BP). As an early event in the regulatory cascade, cellular iron deprivation induces the IRE-binding activity of IRE-BP, whereas binding activity is reduced in iron-replete cells. IRE-BP is highly homologous to the iron-sulphur (Fe-S) protein aconitase which strongly suggests that IRE-BP is an Fe-S protein itself. Control over IRE-BP activity by the cellular iron status is exerted post-translationally and likely involves changes between (4Fe-4S) and (3Fe-4S) states of the postulated IRE-BP Fe-S cluster. In addition, post-translational regulation of IRE-BP activity via heme has been proposed. Subsequent to its activation, IRE-BP binds with high affinity to single IREs contained in the 5' untranslated regions (UTRs) of ferritin and erythroid 5-aminolevulinic acid synthase (eALAS) mRNAs. The binding represses translation of these proteins involved in iron storage and utilization, respectively. In contrast, iron uptake is largely regulated via multiple IREs in the 3' UTR of transferrin receptor (TfR) mRNA. TfR-IREs are required for the iron-sensitive control of TfR mRNA stability. IRE-BP binding stabilizes TfR gene transcripts against as yet undefined ribonucleases. As a result of these regulatory interactions, iron starvation induces the expression of TfR, thereby increasing iron uptake, and represses the synthesis of proteins involved in iron storage and utilization. As cellular iron levels rise, the homeostatic balance is maintained by lowering iron uptake and increasing iron storage in ferritin.
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PMID:Coordination of cellular iron metabolism by post-transcriptional gene regulation. 143 80

The anatomical and cellular distribution of non-haem iron, ferritin, transferrin, and the transferrin receptor have been studied in postmortem human brain and these studies, together with data on the uptake and transport of labeled iron, by the rat brain, have been used to elucidate the role of iron and other metal ions in certain neurological disorders. High levels of non-haem iron, mainly in the form of ferritin, are found in the extrapyramidal system, associated predominantly with glial cells. In contrast to non-haem iron, the density of transferrin receptors is highest in cortical and brainstem structures and appears to relate to the iron requirement of neurones for mitochondrial respiratory activity. Transferrin is synthesized within the brain by oligodendrocytes and the choroid plexus, and is present in neurones, consistent with receptor mediated uptake. The uptake of iron into the brain appears to be by a two-stage process involving initial deposition of iron in the brain capillary endothelium by serum transferrin, and subsequent transfer of iron to brain-derived transferrin and transport within the brain to sites with a high transferrin receptor density. A second, as yet unidentified mechanism, may be involved in the transfer of iron from neurones possessing transferrin receptors to sites of storage in glial cells in the extrapyramidal system. The distribution of iron and the transferrin receptor may be of relevance to iron-induced free radical formation and selective neuronal vulnerability in neurodegenerative disorders.
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PMID:Brain iron homeostasis. 143 85

The iron-responsive element binding protein (IRE-BP) interacts with specific sequence/structure motifs (iron-responsive elements) within the mRNAs encoding ferritin and the transferrin receptor and thereby post-transcriptionally regulates the expression of these two proteins involved in cellular iron homeostasis. The activity of the IRE-BP is itself regulated by iron such that when cells are treated with an iron source, the RNA binding activity is decreased. The expression of recombinant human IRE-BP in murine cells has been examined as have the expressions of the endogenous IRE-BP of both human and rabbit cells. In all cases, iron down-modulated the RNA binding activity of the IRE-BP, but in no instance was this decrease in activity accompanied by a decrease in the level of the protein as judged by quantitative Western blots. Moreover, the rate of synthesis of the IRE-BP and its rate of degradation have been found to be unaltered by iron manipulation of cells in culture. Consistent with IRE-BP regulation occurring post-translationally, the iron regulation of its activity was found to be unaffected by cycloheximide. These data are discussed in terms of a model of IRE-BP regulation involving the modification of the protein's iron-sulfur center.
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PMID:Iron regulates the activity of the iron-responsive element binding protein without changing its rate of synthesis or degradation. 144 94

We used lipopolysaccharide (LPS) to provoke immune responses and observed the changes in the localization of iron and iron-related proteins, such as transferrin receptor, ferritin and hemosiderin in the rat spleen. After intravenous injection of 250 micrograms LPS (salmonella minnesota R595), spleen weight and serum IgM levels increased, cells incorporating 5-bromo-2'-deoxyuridine (BrdU), and transferrin receptor positive cells increased in the peripheral portion of the periarterial lymphoid sheath (PALS), the marginal zone (MZ) and the follicles. Ferritin positive cells increased markedly in the white pulp and stainable iron increased in the marginal metallophils (MM) and in the macrophages in the MZ and the outer PALS. Even in iron deficient rats, a similar change was observed for the localization of iron and iron-related proteins after injection of LPS. After injection of 0.4 mg keyhole limpet hemocyanin (KLH), changes similar to but less pronounced than that in the LPS injected rats were observed for serum IgM levels and for the localization of iron and iron-related proteins. These results showed that the iron in the MM and the macrophages in the white pulp have a dynamic response to immunological challenges and suggested that they play some role in immune responses.
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PMID:Mobilization of iron and iron-related proteins in rat spleen after intravenous injection of lipopolysaccharides (LPS). 144 84

In order to further study the relation between transferrin receptor and erythropoiesis we examined serum receptor levels in megaloblastic anemia, which is the classic example of ineffective erythropoiesis. We studied 33 patients with unequivocal cobalamin deficiency, only 22 of whom were anemic. High serum transferrin receptor levels were found in 12 patients, all of whom were anemic and had high lactate dehydrogenase (LDH) levels; in contrast, only 10 of the 21 patients with normal receptor levels were anemic. Receptor correlated most strongly with LDH (r = 0.573, p < 0.001) and, inversely, with hemoglobin values (r = -0.560, p < 0.001); it also correlated with ferritin and total bilirubin levels, but not with cobalamin, MCV or erythropoietin. No association was found with the hemolytic component of megaloblastic anemia, represented indirectly by haptoglobin levels. Changes induced by cobalamin therapy were also examined in 13 patients. Transferrin receptors rose in all 6 patients who initially had high levels and in 2 of 3 patients who had borderline levels, but not in the 4 patients with initially normal levels. The receptor levels began to rise within 1-3 days, peaked at about 2 weeks and returned to normal at about the 5th wk. The findings indicate that serum transferrin receptor levels reflect the severity of the megaloblastic anemia. The elevated receptor levels rise further with cobalamin therapy, however, as effective erythropoiesis replaces ineffective erythropoiesis, and these persist until the increased erythropoiesis returns to normal.
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PMID:Serum transferrin receptor in the megaloblastic anemia of cobalamin deficiency. 147 86

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