Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The divalent metal transporter (DMT1, also known as NRAMP2 or DCT1) is the likely target for regulation of intestinal iron absorption by iron stores. We investigated changes in intestinal DMT1 expression after a bolus of dietary iron in iron-deficient Belgrade rats homozygous for the DMT1 G185R mutation (b/b) and phenotypically normal heterozygous littermates (+/b). Immunofluorescent staining with anti-DMT1 antisera showed that DMT1 was located in the brush-border membrane. Duodenal DMT1 mRNA and protein levels were six- and twofold higher, respectively, in b/b rats than in +/b rats. At 1.5 h after dietary iron intake in +/b and b/b rats, DMT1 was internalized into cytoplasmic vesicles. At 1.5 and 3 h after iron intake in +/b and b/b rats, there was a rapid decrease of DMT1 mRNA and a transient increase of DMT1 protein. The decrease of DMT1 mRNA was specific, because ferritin mRNA was unchanged. After iron intake, an increase in ferritin protein and decrease in iron-regulatory protein binding activity occurred, reflecting elevated intracellular iron pools. Thus intestinal DMT1 rapidly responds to dietary iron in both +/b and b/b rats. The internalization of DMT1 may be an acute regulatory mechanism to limit iron uptake. In addition, the results suggest that in the Belgrade rat DMT1 with the G185R mutation is not an absolute block to iron.
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PMID:Dietary iron induces rapid changes in rat intestinal divalent metal transporter expression. 1105 5

Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs. The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H(2)O(2) that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 microm H(2)O(2) for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H(2)O(2) induces a approximately 4-fold increase in TfR mRNA levels within 2-6 h, and subsequent accumulation of newly synthesized protein after 4 h. This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells. Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the Divalent Metal Transporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs. Finally, H(2)O(2)-treated cells display an increased capacity to sequester (59)Fe in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of (59)Fe intracellular distribution. Our data suggest that H(2)O(2) regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.
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PMID:Modulation of cellular iron metabolism by hydrogen peroxide. Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts. 1126 85

With rare exceptions, virtually all studied organisms from Archaea to man are dependent on iron for survival. Despite the ubiquitous distribution and abundance of iron in the biosphere, iron-dependent life must contend with the paradoxical hazards of iron deficiency and iron overload, each with its serious or fatal consequences. Homeostatic mechanisms regulating the absorption, transport, storage and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. A coherent understanding of that biology and chemistry is now rapidly emerging. In this review we will emphasize discoveries of the past decade, which have brought a revolution to the understanding of the molecular events in iron metabolism. Of central importance has been the discovery of new proteins carrying out functions previously suspected but not understood or, more interestingly, unsuspected and surprising. Parallel discoveries have delineated regulatory mechanisms controlling the expression of proteins long known--the transferrin receptor and ferritin--as well as proteins new to the scene of iron metabolism and its homeostatic control. These proteins include the iron regulatory proteins (IRPs 1 and 2), a variety of ferrireductases in yeast an mammalian cells, membrane transporters (DMT1 and ferroportin 1), a multicopper ferroxidase involved in iron export from cells (hephaestin), and regulators of mitochondrial iron balance (frataxin and MFT). Experimental models, making use of organisms from yeast through the zebrafish to rodents have asserted their power in elucidating normal iron metabolism, as well as its genetic disorders and their underlying molecular defects. Iron absorption, previously poorly understood, is now a fruitful subject for research and well on its way to detailed elucidation. The long-sought hemochromatosis gene has been found, and active research is underway to determine how its aberrant functioning results in disease that is easily controlled but lethal when untreated. A surprising connection between iron metabolism and Friedreich's ataxia has been uncovered. It is no exaggeration to say that the new understanding of iron metabolism in health and disease has been explosive, and that what is past is likely to be prologue to what is ahead.
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PMID:Chemistry and biology of eukaryotic iron metabolism. 1147 Feb 29

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.
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PMID:Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism. 1170 34

Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding tranferrin-mediated iron uptake. However, it was not until recently with the identification and characterization of several new genes related to iron homeostasis, such as the hemochromatosis protein HFE and the iron transporter DMT1, that our knowledge has been advanced dramatically. A major pathway for cellular iron uptake is through internalization of the complex of iron-bound transferrin and the transferrin receptor, which is negatively modulated by HFE, a protein related to hereditary hemochromatosis. Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1. The iron is then utilized as a cofactor by heme and ribonucleotide reductase or stored in ferritin. Apart from iron, many other metal ions of therapeutic and diagnostic interests can also bind to transferrin at the iron sites and their transferrin complexes can be recognized by many cells. Therefore, transferrin has been thought as a "delivery system" for many beneficial and harmful metal ions into the cells. Transferrin has also be widely applied as a targeting ligand in the active targeting of anticancer agents, proteins, and genes to primary proliferating malignant cells that overexpress transferrin receptors. This is achieved by conjugation of transferrin with drugs, proteins, hybride systems with marcomolecules and as liposomal-coated systems. Conjugates of anticancer drugs with transferrin can significantly improve the selectivity and toxicity and overcome drug resistance, thereby leading to a better treatment. The coupling of DNA to transferrin via a polycation such as polylysine or via cationic liposomes can target and transfer of the extrogenous DNA particularly into proliferating cells through receptor-mediated endocytosis. These kinds of non-viral vectors are potential alternatives to viral vectors for gene therapy, if the transfection efficiency can be improved. Moreover, transferrin receptors have shown potentials in delivery of therapeutic drugs or genes into the brain across blood-brain barrier.
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PMID:Transferrin/transferrin receptor-mediated drug delivery. 1193 19

Hereditary hemochromatosis is characterized by marked variation of expression of the defect: very few homozygotes with the C282Y/C282Y HFE genotype have full-blown clinical disease, a larger number show biochemical stigmata of iron overload, and some seem normal biochemically. The following candidate genes have been examined in detail to determine whether polymorphisms in them may be responsible for this variation: transferrin, transferrin receptor 1, transferrin receptor 2, ferritin-L, ferritin-H, IRP1, IRP2, HFE, beta(2) microglobulin, mobilferrin/calreticulin, ceruloplasmin, ferroportin, NRAMP1, NRAMP2 (DMT1), haptoglobin, heme oxygenase-1, heme oxygenase-2, hepcidin, USF2, ZIRTL, duodenal cytochrome b ferric reductase (DCYTB), TNFalpha, keratin 8, and keratin 18. The coding sequence, exon-intron junctions, and promoters of each of these genes was sequenced in DNA from 20 subjects: 5 HFE C282Y/C282Y with clinical disease, 5 HFE C282Y/C282Y with normal/low ferritin levels and no disease, 5 wt/wt with high ferritin and transferrin saturation, and 5 wt/wt normal controls. When coding or promoter polymorphisms were encountered, DNA from large numbers of ethnically defined subjects was examined for these polymorphisms and a relationship between their existence and abnormalities of iron homeostasis was sought. Only in the case of one transferrin mutation did we find a strong relationship between the polymorphism and iron deficiency anemia. The putative genes that affect the expression of HFE mutations remain elusive.
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PMID:Seeking candidate mutations that affect iron homeostasis. 1254 38

Release of iron from enterocytes and hepatocytes is thought to require the copper-dependent ferroxidase activity of hephaestin (Hp) and ceruloplasmin (Cp), respectively. In swine, copper deficiency (CD) impairs iron absorption, but whether this occurs in rats is unclear. By feeding a diet deficient in copper, CD was produced, as evidenced by the loss of copper-dependent plasma ferroxidase I activity, and in enterocytes, CD reduced copper levels and copper-dependent oxidase activity. Hematocrit was reduced, and liver iron was doubled. CD reduced duodenal mucosal iron and ferritin, whereas CD increased iron absorption. Duodenal mucosal DMT1-IRE and ferroportin1 expression remained constant with CD. When absorption in CD rats was compared with that seen normally and in iron-deficient anemic animals, strong correlations were found among mucosal iron, ferritin, and iron absorption, suggesting that the level of iron absorption was appropriate given that the erythroid and stores stimulators of iron absorption are opposed in CD. Because CD reduced the activity of Cp, as evidenced by copper-dependent plasma ferroxidase I activity and hepatocyte iron accumulation, but iron absorption increased, it is unlikely that the ferroxidase activity of Hp is important and suggests another function for this protein in the export of iron from the enterocyte during iron absorption. Also, the copper-dependent ferroxidase activity of Cp does not appear important for iron efflux from macrophages, because Kupffer cells of the liver and nonheme iron levels of the spleen were normal during copper deficiency, suggesting another role for Cp in these cells.
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PMID:Copper deficiency increases iron absorption in the rat. 1276 Sep 4

Hepatic hemosiderosis and increased iron absorption are common findings in cirrhosis. It has been proposed that a positive relation exists between intestinal iron absorption and the development of hepatic hemosiderosis. The current study investigated the duodenal expression of the iron transport molecules divalent metal transporter 1 (DMT1 [IRE]), iron-regulated gene 1 (Ireg1 [ferroportin]), hephaestin, and duodenal cytochrome b (Dyctb) in 46 patients with cirrhosis and 20 control subjects. Total RNA samples were extracted from duodenal biopsy samples and the expression of the iron transport genes was assessed by ribonuclease protection assays. Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects. The presence of cirrhosis per se and serum ferritin (SF) concentration were independent factors that influenced the expression of DMT1. However, only SF concentration was independently associated with Ireg1 expression. In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type. There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis. In conclusion, the presence of cirrhosis is an independent factor associated with increased expression of DMT1 but not Ireg1. The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined. Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload.
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PMID:Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis. 1476 3

Neurons need iron, which is reflected in their expression of the transferrin receptor. The concurrent expression of the ferrous iron transporter, divalent metal transporter I (DMT1), in neurons suggests that the internalization of transferrin is followed by detachment of iron within recycling endosomes and transport into the cytosol via DMT1. To enable DMT1-mediated export of iron from the endosome to the cytosol, ferric iron must be reduced to its ferrous form, which could be mediated by a ferric reductase. The presence of nontransferrin-bound iron in brain extracellular fluids suggests that neurons can also take up iron in a transferrin-free form. Neurons are thought to be devoid of ferritin in many brain regions in which there is an association between iron accumulation and cellular damage, for example, neurons of the substantia nigra pars compacta. The general lack of ferritin together with the prevailing expression of the transferrin receptor indicates that iron acquired by activity of transferrin receptors is directed toward immediate use in relevant metabolic processes, is exported, or is incorporated into complexes other than ferritin. Iron has long been considered to play a significant role in exacerbating degradation processes in brain tissue subjected to acute damage and neurodegenerative disorders. In brain ischemia, the damaging role of iron may depend on the inhibition of detoxifying enzymes responsible for catalyzing the oxidation of ferrous iron. Brain ischemia may also lead to an increase in iron supply to neurons as transferrin receptor expression by brain capillary endothelial cells is increased. Pharmacological blockage of the transferrin receptor/DMT1-mediated uptake could be a target to prevent further iron uptake. In chronic neurodegenerative settings, a deleterious role of iron is suggested since cases of Alzheimer's disease, Parkinson's disease, and Huntington's disease have a significantly higher accumulation of iron in affected regions. Dopaminergic neurons are rich in neuromelanin, shown to be more redox-active in Parkinson's disease cases. Iron-containing inflammatory cells may, however, account for the main portion of iron present in neurodegenerative disorders. More knowledge about iron metabolism in normal and diseased neurons is warranted as this may identify pharmaceutical targets to improve neuronal iron management.
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PMID:The metabolism of neuronal iron and its pathogenic role in neurological disease: review. 1510 52

Iron, the major trace element in the body, is an essential component of many proteins and enzymes. As low-molecular-weight iron is potentially toxic to cells, higher organisms express a number of proteins for the transport and storage of iron. We review our current understanding of the intestinal absorption of iron in the light of recently identified membrane proteins, namely the ferrric reductase, Dcytb, the two iron(II) transport proteins, DMT1 and ferroportin/Ireg1, and hephaestin, the membrane-bound homologue of the ferroxidase ceruloplasmin. Two types of mammalian transferrin receptor, TfR1 and TfR2, are now known to exist. The structure of TfR1 and its role in the process of receptor-mediated cellular uptake of iron are presented together with structural information on the iron storage protein ferritin. Mechanisms for the regulation of levels of TfR1 and ferritin, as well as other proteins involved in iron homeostasis, are discussed. Our current knowledge and understanding of the structure of members of the transferrin family of iron-binding proteins and the nature of the iron-binding centres in transferrins is presented, together with information on the processes of iron-uptake and iron-release by transferrin and a summary of the elements that have been found to bind to transferrins.
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PMID:Structure/function overview of proteins involved in iron storage and transport. 1630 65


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