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

Intracellular levels of the light (L) and heavy (H) ferritin subunits are regulated by iron at the level of message translation via a modulated interaction between the iron regulatory proteins (IRP1 and IRP2) and a 5'-untranslated region. Iron-responsive element (IRE). Here we show that iron and interleukin-1beta (IL-1beta) act synergistically to increase H- and L-ferritin expression in hepatoma cells. A GC-rich cis-element, the acute box (AB), located downstream of the IRE in the H-ferritin mRNA 5'-untranslated region, conferred a substantial increase in basal and IL-1beta-stimulated translation over a similar time course to the induction of endogenous ferritin. A scrambled version of the AB was unresponsive to IL-1. Targeted mutation of the AB altered translation; reverse orientation and a deletion of the AB abolished the wild-type stem-loop structure and abrogated translational enhancement, whereas a conservative structural mutant had little effect. Labeled AB transcripts formed specific complexes with hepatoma cell extracts that contained the poly(C)-binding proteins, iso-alphaCP1 and -alphaCP2, which have well defined roles as translation regulators. Iron influx increased the association of alphaCP1 with ferritin mRNA and decreased the alphaCP2-ferritin mRNA interaction, whereas IL-1beta reduced the association of alphaCP1 and alphaCP2 with H-ferritin mRNA. In summary, the H-ferritin mRNA AB is a key cis-acting translation enhancer that augments H-subunit expression in Hep3B and HepG2 hepatoma cells, in concert with the IRE. The regulated association of H-ferritin mRNA with the poly(C)-binding proteins suggests a novel role for these proteins in ferritin translation and iron homeostasis in human liver.
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PMID:The acute box cis-element in human heavy ferritin mRNA 5'-untranslated region is a unique translation enhancer that binds poly(C)-binding proteins. 1596 98

Ferritin, the main iron storage protein, exerts a cytoprotective effect against the iron-catalyzed production of reactive oxygen species, but its role in brain injury caused by hypoxia/reoxygenation is unclear. Ferritin expression is regulated mainly at post-transcriptional level by iron regulatory proteins (IRP1 and IRP2) that bind specific RNA sequences (IREs) in the 5'untranslated region of ferritin mRNA. Here, we show that hypoxia decreases IRP1 binding activity in glial cells and enhances it in cortical neurons. These effects were reversed by reoxygenation in both cell types. In glial cells there was an early increase of ferritin synthesis during hypoxia and reoxygenation. Conversely, in cortical neurons, ferritin synthesis increased during the late phase of reoxygenation. Steady-state analysis of ferritin mRNA levels suggested that ferritin synthesis is regulated mainly post-transcriptionally by IRPs in glioma cells, both transcriptionally and post-transcriptionally in type-1 astrocytes, and mainly at transcriptional level in an IRP-independent way in neurons. The different regulation of ferritin expression may account for the different vulnerability of neurons and glial cells to the injury elicited by oxygen and glucose deprivation (OGD)/reoxygenation. The greater vulnerability of cortical neurons to hypoxia-reoxygenation was strongly attenuated by the exogenous administration of ferritin during OGD/reoxygenation, suggesting the possible cytoprotective role exerted by this iron-segregating protein.
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PMID:Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells. 1613 72

Iron regulatory proteins (IRP1 and 2) function as translational regulators that coordinate the cellular iron metabolism of eukaryotes by binding to the mRNA of target genes such as the transferrin receptor or ferritin. In addition to IRP2, IRP1 serves as sensor of reactive oxygen species (ROS). As iron and oxygen are essential but potentially toxic constituents of most organisms, ROS-mediated modulation of IRP1 activity may be an important regulatory element in dissecting iron homeostasis and oxidative stress. The responses of IRP1 towards reactive oxygen species are compartment-specific and rather complex: H2O2 activates IRP1 via a signaling cascade that leads to upregulation of the transferrin receptor and cellular iron accumulation. Contrary, superoxide inactivates IRP1 by a direct chemical attack being limited to the intracellular compartment. In particular, activation of IRP1 by H2O2 has established a new regulatory link between inflammation and iron metabolism with new clinical implications. This mechanism seems to contribute to the anemia of chronic disease and inflammation-mediated iron accumulation in tissues. In addition, the cytotoxic side effects of redox-cycling anticancer drugs such as doxorubicin may involve H2O2-mediated IRP1 activation. These molecular insights open up new therapeutic strategies for the clinical management of chronic inflammation and drug-mediated cardiotoxicity.
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PMID:Iron regulatory protein 1 as a sensor of reactive oxygen species. 1640 78

A central role of iron in the pathogenesis of Parkinson's disease (PD) has been discussed for many years. So far, however, a biomarker indicating increased iron levels in the substantia nigra (SN) in PD patients has been missing. Performing transcranial ultrasound we detected an increased area of SN echogenicity as a typical echofeature in PD, visible already in the early stages of the disease and in subjects with subclinical impairment of the nigrostriatal system. Animal studies and post mortem analyses of human brain tissue revealed that this echofeature is associated with increased iron levels of the substantia nigra as well as a reduced neuromelanin content. The apparently autosomal dominant inheritance of this echofeature in relatives of patients with idiopathic PD indicates a primary role of disturbances of iron metabolism in PD. Consequently performed mutation analyses in genes involved in brain iron metabolism lead to the discovery of specific mutations in the ferritin-H, IRP2 and HFE gene in single PD patients. Moreover, variations in the ceruloplasmin gene were found to be associated with PD or SN hyperechogenicity. Functional relevance of some of these mutations for iron metabolism could be proven. Therefore, SN hyperechogenicity can be regarded as biomarker for both: impairment of the nigrostriatal system and increased iron levels of the SN. Future studies aim at substantiating the hypothesis that healthy subjects with SN hyperechogenicity indeed represent a population at risk for nigrostriatal degeneration, which would have a significant impact on therapeutical options.
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PMID:Disturbance of iron metabolism in Parkinson's disease -- ultrasonography as a biomarker. 1646 47

Iron regulatory proteins 1 and 2 (IRPs) are homologous mammalian cytosolic proteins that sense intracellular iron levels and post-transcriptionally regulate expression of ferritin, transferrin receptor, and other iron metabolism proteins. Adult mice with homozygous targeted deletion of IRP2 develop microcytic anemia, elevated red cell protoporphyrin IX levels, high serum ferritin, and adult-onset neurodegeneration. Mice with homozygous deletion of IRP1 develop no overt abnormalities, but mice that lack both copies of IRP2 and one copy of IRP1 develop a more severe anemia and neurodegeneration than mice with deletion of IRP2 alone. Here, we have demonstrated that IRP1-/- IRP2-/- embryos do not survive gestation, and that although IRP1-/- IRP2-/blastocysts can be genotyped and harvested, implanted embryos with the IRP1-/- IRP2-/genotype are undetectable at embryonic day 6.5 and beyond. Blastocysts derived from a cross in which 25% of the fertilized embryos were expected to have the IRP1-/- IRP2-/genotype often showed brown discoloration and abnormal morphology. These abnormal blastocysts likely have the IRP1-/- IRP2-/- genotype, and the brown discoloration may be attributable to ferritin overexpression and sequestration of ferric iron in ferritin, whereas abnormal morphology may be due to concomitant functional iron deficiency. These results demonstrate that IRPs are indispensable for regulation of mammalian iron homeostasis at the post-implantation stage of murine embryonic development.
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PMID:Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. 1648 Sep 4

Patients with alcoholic liver disease frequently exhibit iron overload in association with increased hepatic fibrosis. Even moderate alcohol consumption elevates body iron stores; however, the underlying molecular mechanisms are unknown. Hepcidin, a circulatory peptide synthesized in the liver, is a key mediator of iron metabolism. Ethanol metabolism significantly down-regulated both in vitro and in vivo hepcidin mRNA and protein expression. 4-Methylpyrazole, a specific inhibitor of the alcohol-metabolizing enzymes, abolished the effects of ethanol on hepcidin. However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNA-binding proteins, IRP1 and IRP2. Mice maintained on 10-20% ethanol for 7 days displayed down-regulation of liver hepcidin expression without changes in liver triglycerides or histology. This was accompanied by elevated duodenal divalent metal transporter1 and ferroportin protein expression. Injection of hepcidin peptide negated the effect of ethanol on duodenal iron transporters. Ethanol down-regulated hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein alpha (C/EBPalpha) but not beta. Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBPalpha binding activity and hepcidin expression in the liver and the up-regulation of duodenal divalent metal transporter 1. Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBPalpha, which in turn leads to increased duodenal iron transport.
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PMID:Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. 1725 19

Iron aggravates the cardiotoxicity of doxorubicin (DOX), a widely used anticancer anthracycline. The amount of iron in the cell is regulated by the iron regulatory proteins (IRPs)-1 and -2 that control the posttranscriptional expression of key iron metabolism genes. In vitro and cell culture studies revealed the ability of DOX to modulate the activity of both IRPs. However, conflicting data were obtained from different cell types and experimental conditions. To investigate the connection between acute DOX cardiotoxicity and the IRPs in a mammalian organism, we analyzed IRP activity and the expression of IRP target genes in the heart of mice subjected to DOX treatment. DOX exposure elicits a differential modulation of the two IRPs with reduced IRP2 activity and unchanged IRP1 activity. IRP2 downmodulation is associated with the upregulation of the ferritin L and H genes and decreased expression of the transferrin receptor 1 (TfR1). To directly test the role of IRP1 in DOX cardiotoxicity, the DOX response was analyzed in mice lacking IRP1. DOX-mediated IRP2 downmodulation and regulation of ferritin and TfR1 expression is identical in Irp1 (-/-) mice compared to wild type, as is the degree of oxidative damage of the heart assessed by thioredoxin and thiobarbituric acid reactive substance levels and by brain natriuretic peptide mRNA expression. These data demonstrate that the alterations of cardiac iron homeostasis related to acute anthracycline cardiotoxicity occur independently of IRP1. The observed IRP2 downmodulation could serve as a means to counteract DOX cardiotoxicity by reducing the "free" cellular iron pool.
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PMID:IRP1-independent alterations of cardiac iron metabolism in doxorubicin-treated mice. 1677 Jun 44

The iron regulatory proteins (IRP1 and IRP2) are two cytoplasmic RNA-binding proteins that control iron metabolism in mammalian cells. Both IRPs bind to specific sequences, called iron-responsive elements (IREs), located in the 3' or 5' untranslated regions (UTR) of several mRNAs, in particular the mRNA encoding ferritin subunits and transferrin receptor. At low intracellular iron concentration, IRPs bind to the IRE of ferritin mRNA at its 5'-UTR and block translation, whereas they stabilize transferrin receptor mRNA through direct interactions with several IRE motifs in the 3'-UTR. The converse regulation of ferritin and TfR synthesis, resulting from lack of binding of IRPs to IRE, occurs in cells with high iron level. In both, iron deficiency and excess IRP-mediated regulation rapidly restore the physiological cytosolic iron level. The role of IRPs in maintaining the intracelluar iron balance has been well characterized in numerous types of mammalian cells in culture. However, the importance of IRPs in the regulation of systemic iron metabolism in mammals, in particular in signaling between cells which play major roles in body iron metabolism, such as duodenal enterocytes, reticuloendothelial macrophages, hepatocytes, and bone marrow precursors of red blood cells, is only beginning to be investigated. This review presents the basic features of iron metabolism in IRP1 and IRP2 knockout mice and focuses on how recent studies on these animal models have advanced our understanding of the role of IRPs in iron mammalian physiology.
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PMID:[The role of iron regulatory proteins (IRPs) in the regulation of systemic iron homeostasis: lessons from studies on IRP1 and IRP2 knock out mice]. 1681 31

Ferritin gene expression is complex and is controlled at transcriptional level in response to a variety of stimuli such as hormones, cytokines and cAMP. Iron, hemin and several compounds, chemically different, also activate the transcription of the ferritin gene. Ferritin biosynthesis is mainly regulated at post-transcriptional level by iron regulatory proteins (IRP1 and IRP2). We previously reported that oxalomalate, a competitive inhibitor of aconitase, remarkably decreases the IRP1 RNA-binding activity and induces a significant increase of ferritin expression. Here, we examined in cells cultured in presence of OMA the IRP1 intracellular content, ferritin biosynthesis and the transcriptional efficiency of H-ferritin gene promoter. Our results demonstrate a peculiar role of OMA that rapidly inactivates IRP1 without affecting IRP1 protein content and subsequently activates H-ferritin gene transcription leading to an overall increase of ferritin biosynthesis. We conclude that OMA regulates H-ferritin biosynthesis acting early at the post-transcriptional level and later on at transcriptional level.
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PMID:Induction of H-ferritin synthesis by oxalomalate is regulated at both the transcriptional and post-transcriptional levels. 1682 96

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.
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PMID:The role of iron regulatory proteins in mammalian iron homeostasis and disease. 1685 17


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