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

At least two groups of eukaryotic mRNAs (ferritin and erythroid 5-aminolevulinate synthase) are translationally regulated via iron-responsive elements (IREs) located in a conserved position within the 5' untranslated regions of their mRNAs. We establish that the spacing between the 5' terminus of an mRNA and the IRE determines the potential of the IRE to mediate iron-dependent translational repression. The length of the RNA spacer rather than its nucleotide sequence or predicted secondary structure is shown to be the primary determinant of IRE function. When the position of the IRE is preserved, sequences flanking the IRE in natural ferritin mRNA can be replaced by altered flanking sequences without affecting the regulatory function of the IRE in vivo. These results define position as a critical cis requirement for IRE function in vivo and imply the potential to utilize transcription start site selection to modulate the function of this translational regulator.
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PMID:Position is the critical determinant for function of iron-responsive elements as translational regulators. 156 33

The iron-responsive element-binding protein (IRE-BP) is an RNA-binding protein that regulates the expression of several mRNAs in response to availability of cellular iron. The iron-dependent control of IRE-BP activity has been reconstituted in vitro. Incubation of purified IRE-BP with iron salts in the presence of the reducing agent cysteine decreases IRE-BP binding to the cognate RNA element. The specificity of this effect is established by several parameters: (i) the interaction of the spliceosomal protein U1A with its U1 small nuclear RNA target sequence as an internal control is unaffected by iron perturbations, (ii) non-iron metals fail to mimic the iron effect, and (iii) iron chelator activates the IRE-binding activity of IRE-BP and titrates the effect of iron salts. Modulation of IRE-BP activity by chelatable iron is reversible and thus does not involve permanent alterations of the integrity of the protein. These findings accurately mirror the physiological basis for iron regulation of transferrin receptor mRNA stability as well as ferritin and erythroid 5-aminolevulinate synthase mRNA translation in vivo. We discuss these data vis-a-vis the structural homology of IRE-BP with the iron-sulfur protein aconitase and propose a mechanism by which the same cytoplasmic protein serves a dual function as an RNA-binding factor and an enzyme.
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PMID:Modulation of the RNA-binding activity of a regulatory protein by iron in vitro: switching between enzymatic and genetic function? 158 91

Iron-responsive elements (IREs) are regulatory RNA elements which are characterized by a phylogenetically defined sequence-structure motif. Their biological function is to provide a specific binding site for the IRE-binding protein (IRE-BP). Iron starvation of cells induces high affinity binding of the cytoplasmic IRE-BP to an IRE which has at least two different known biological consequences, repression of ferritin mRNA translation and stabilization of the transferrin receptor transcript. We report the identification of a novel, evolutionarily conserved IRE motif in the 5' UTR of murine and human erythroid-specific delta-aminolevulinic acid synthase (eALAS) mRNA which encodes the first, and possibly rate limiting, enzyme of the heme biosynthetic pathway. We demonstrate the function of the eALAS IRE as a specific binding site for the IRE-BP by gel retardation analyses and by in vitro translation experiments. In addition, we show that the 5' UTR of eALAS mRNA is sufficient to mediate iron-dependent translational regulation in vivo. These findings strongly suggest involvement of the IRE-IRE-BP system in the control of heme biosynthesis during erythroid differentiation.
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PMID:Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA. 205 Jan 26

The aim of this study was to investigate a possible relationship between exposure to sulfides and disturbances of the synthesis of heme and the erythrocytes. Eighteen workers exposed to sulfides at a pulp and paper plant were examined and compared with individually matched referents from a thermomechanical pulp plant without such exposure. The exposure levels of methylmercaptan, dimethylsulfide, and dimethyldisulfide were low. However, five subjects were exposed to high levels of short duration, and their data were analyzed separately. The activity of the enzymes delta-aminolevulinic acid synthase and heme synthase in reticulocytes, characteristics of the erythrocytes, and the iron status were analyzed. A minor decrease, not statistically significant, was observed for the enzymes among the five highly exposed subjects. However, the concentrations of iron and transferrin were elevated and the concentration of ferritin was low in comparison to the corresponding levels of the referents. This combination will not occur spontaneously. A previous study indicated that sulfides may inhibit heme synthesis, and the present study suggests that they may also disturb iron metabolism.
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PMID:Disturbed iron metabolism among workers exposed to organic sulfides in a pulp plant. 335 91

Acute iron loading of rats, by intraperitoneal administration of iron-dextran (500 mg Fe/kg body wt 18-20 h before killing) decreased by 30% the rate of conversion of 5-amino-[14C]levulinate ([14C]ALA) into heme as measured with a recently described procedure for liver homogenates (1981. Biochem. J. 198: 595-604). The decrease in conversion of labeled ALA into heme caused by iron loading was shown to be due to a 70-80% decrease in activity of ALA dehydrase. The decrease in activity of ALA dehydrase caused by iron loading was not associated with a decrease in hepatic concentrations of GSH, nor could it be reversed by addition of dithiothreitol, Zn2+ or chelators of Fe2+ and Fe3+. Addition of FeSO4, ferric citrate, or ferritin to homogenates of control liver had no effect of activity of ALA dehydrase. The decrease in activity of ALA dehydrase, caused by iron-dextran, was mirrored by a reciprocal increase in ALA synthase. Iron-dextran potentiated the induction of ALA synthase by allylisopropylacetamide. However, this potentiation could be dissociated from the decrease in ALA dehydrase caused by iron loading.
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PMID:Iron and the liver: acute effects of iron-loading on hepatic heme synthesis of rats. Role of decreased activity of 5-aminolevulinate dehydrase. 618 58

Iron metabolism and its molecular regulation are reviewed. Ferric iron is bound to mucin in the stomach and delivered to the duodenum where it can be absorbed. Iron is transported across the apical membrane of the gut mucosa by integrin. Once within the mucosal cell, iron may be stored, utilized in protein synthesis, or exported to the serum. In the serum, iron is carried by transferrin. Diferric transferrin binds to transferrin receptor on the surface of cells and is endocytosed. In the cell, iron is bound to high and low molecular weight ligand and is thought to shuttle iron within the cell. Iron can be stored intracellularly within ferritin, or can be utilized in a number of iron containing proteins synthesized by the mitochondrion, including heme, aconitase, and cytochromes. The first chain of enzymes in the biosynthesis of heme is erythroid 5-aminolevulinate synthase (eALAS). Intracellular iron concentration regulates the synthesis of ferritin, transferrin receptor, and eALAS, thus controlling our iron metabolism. Iron regulates these proteins post-transcriptionally via iron responsive elements (IRE), which are highly conserved stem-loop structures found in messenger ribonucleic acid (mRNA), and an IRE binding protein (IRE-BP), which responds to increased intracellular iron concentrations by binding the IRE, and repressing mRNA translation or stabilizing the mRNA, depending on whether the IRE is located in the upstream or downstream untranslated regions of the mRNA. Cellular responses to iron depletion and iron over-load can be explained in terms of these regulatory mechanisms.
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PMID:Iron metabolism and its regulation. A review. 776 65

Cellular iron metabolism comprises pathways of iron-protein synthesis and degradation, iron uptake via transferrin receptor (TfR) or release to the extracellular space, as well as iron deposition into ferritin and remobilization from such stores. Different cell types, depending on their rate of proliferation and/or specific functions, show strong variations in these pathways and have to control their iron metabolism to cope with individual functions. Studies with cultured cells have revealed a specific cytoplasmic protein, called 'iron regulatory protein' (IRP) (previously known as IRE-BP or IRF), that plays a key role in iron homoeostasis by regulating coordinately the synthesis of TfR, ferritin, and erythroid 5-aminolevulinate synthase (eALAS). Present in all tissues analysed, IRP is identical with the [4Fe-4S] cluster containing cytoplasmic aconitase. Under conditions of iron chelation, IRP is an apo-protein which binds with high affinity to specific RNA stem-loop elements (IREs) located 5' of the initiation codon in ferritin and eALAS mRNA, and 3' in the untranslated region of TfR mRNA. At 5' sites IRF blocks mRNA translation, whereas 3' it inhibits TfR mRNA degradation. Both effects compensate for low intracellular iron concentrations. Under high iron conditions, IRP is converted to the holo-protein and dissociates from mRNA. This reverses the control towards less iron uptake and more iron storage. Iron can therefore be considered as a feedback regulator of its own metabolism. It has recently become evident that nitric oxide, produced by macrophages and other cell types in response to interferon-gamma, induces the IRE-binding activity of IRF. Moreover measurements of the RNA-binding activity of IRP in tissue extracts may provide valuable information on iron availability.
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PMID:Molecular regulation of iron proteins. 788 Nov 53

Translation of ferritin and erythroid 5-aminolevulinate synthase (eALAS) mRNAs is regulated by iron via mRNA-protein interactions between iron-responsive elements (IREs) and iron regulatory protein (IRP). In iron-depleted cells, IRP binds to single IREs located in the 5' untranslated regions of ferritin and eALAS mRNAs and represses translation initiation. The molecular mechanism underlying this translational repression was investigated using reconstituted, IRE-IRP-regulated, cell-free translation systems. The IRE-IRP interaction is shown to prevent the association of the 43S translation pre-initiation complex (including the small ribosomal subunit) with the mRNA. Studies with the spliceosomal protein U1A and mRNAs which harbour specific binding sites for this protein in place of an IRE furthermore reveal that the 5' termini of mRNAs are generally sensitive to repressor protein-mediated inhibition of 43S pre-initiation complex binding.
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PMID:Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs. 807 Apr 15

Erythroid cells regulate heme biosynthesis in a manner that is distinct from all other cell types. While heme negatively regulates the synthesis of the housekeeping delta-aminolevulinate synthase (ALAS-N) in all non-erythroid cells, the expression of an erythroid-specific isozyme (ALAS-E) is developmentally regulated in red blood cells. As a first step towards understanding the molecular basis for the transcriptional regulation of ALAS-E during erythropoiesis, we cloned and characterized the chicken ALAS-E locus. This gene spans 18 kbp and is composed of eleven exons. The intron/exon structure of erythroid ALAS was found to be conserved among several vertebrate species. Direct RNA sequencing identified a 5' untranslated region that is derived from two continuous exons and is predicted to form a very stable stem-loop structure that bears resemblance to the ferritin iron-responsive element. Tissue-specific expression of the ALAS-E gene was analyzed by transient transfection assays in hematopoietic cells of both erythroid and non-erythroid origins. These experiments identified distal (-784 to -505 bp) and proximal (-155 to +21 bp) promoter elements which are required for high level, erythroid-specific transcription.
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PMID:Structure and regulation of the chicken erythroid delta-aminolevulinate synthase gene. 816 37

There is a need to change the policy of unselective iron supplementation during periods of life with physiologically increased cell proliferation. Levels of iron stores to be regarded as adequate during infancy and pregnancy are still not well established. Recent data support the view that it is not justified to interfere with physiological adaptations developed through millions of years by sophisticated and precisely coordinated regulation of iron absorption, utilization and storage. Recent data suggest that the chelatable intracellular iron pool regulates the expression of proteins with central importance in cellular iron metabolism (TfR, ferritin, and erythroid 5-aminolevulinic synthetase) in a coordinately controlled way through an iron dependent cytosolic mRNA binding protein, the iron regulating factor (IRF). This factor is simultaneously a sensor and a regulator of iron levels. The reduction of ferritin levels during highly increased cell proliferation is a mirror of the increased density of TfRs. An abundance of data support the vigorous competition for growth-essential iron between microbial pathogens and their vertebrate hosts. The highly coordinated regulation of iron metabolism is probably crucial in achieving a balance between the blockade of readily accessible iron to invading organisms and yet providing sufficient iron for the immune system of the host. The most evident adverse clinical effects of excess iron have been observed in immunodeficient patients in tropical countries and in AIDS patients. Excess iron also increases the risk of initiation and promotion of malignant processes by iron binding to DNA and by the iron-catalysed release of free radicals. Oxygen radicals were shown to damage critical biomolecules leading, apart from cancer, to a variety of human disease states, including inflammation and atherosclerosis. They are also involved in processes of aging and thrombosis. Recent clinical trials have suggested that the use of iron-chelators, natural and synthetic antioxidants, and anti-TfR monoclonal antibodies can contribute in retarding malignant cell proliferation. Hypoferraemia during pregnancy is--like haemodilution--an adaptation to the risks involved in the natural hypercoagulable state of pregnancy. It may also serve to prevent the risk of infections and mutagenicity in the highly proliferating tissues of the foetus. Blunted erythropoiesis has been revealed during the first 30 weeks of pregnancy by the use of the newly developed method of determining the soluble serum transferrin receptor. The lack of increase in erythropoietin levels proves that there is no hypoxia. Decreases in Hb and iron levels are parts of a physiological adaptation. As a consequence they should neither be treated nor prevented. It is stressed that whenever a widespread and ingrained routine medical intervention has to be changed it is essential to first monitor the potential health effects of the recommended change in a national policy.
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PMID:Adequate iron stores and the 'Nil nocere' principle. 824 2


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