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)

Tight regulation of iron metabolism is crucial to avoid formation of deleterious radicals and is mainly executed at the post-transcriptional level. The regulatory loops are exerted by trans-acting iron regulatory proteins (IRPs) and cis-acting stem-loop motifs, termed iron-responsive elements (IREs), located in the untranslated regions (UTRs) of target mRNAs. Iron scarcity induces binding of IRPs to a single IRE in the 5'-UTR of ferritin, eALAS, aconitase and SDHb mRNAs, which specifically suppresses translation initiation. Simultaneous interaction of IRPs with multiple IREs in the 3'-UTR of transferrin receptor (TfR) mRNA selectively causes its stabilization. The pattern is reverted under iron overload: IRP-mRNA binding affinity is reduced, which results in efficient protein synthesis of target transcripts harboring IREs in the 5'-UTR and rapid degradation of TfR mRNA. Although multiple evidences support this model, several studies reported massive alterations in the regulation of iron homeostasis under specific physiological conditions, raising the possibility for additional regulatory events. Intensive analysis of the palindromic IRE consensus sequence revealed the critical elements for the formation of a functional structure and demonstrated the consequences of IRE mutations in IRP binding. Recent investigations indicated the involvement of naturally occurring IRE mutations of the ferritin L subunit in the hyperferritinemia-cataract syndrome, a hereditary disorder. This review summarizes the apparent links between iron-dependent post-transcriptional control and its abnormalities, governed by the properties of a single mRNA stem-loop structure.
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PMID:Post-transcriptional control via iron-responsive elements: the impact of aberrations in hereditary disease. 1059 29

A family of non-coding sequences in the mRNA (iso-IREs [iron-responsive elements]) regulate synthesis of key proteins in animal iron and oxidative metabolism such as ferritin and mitochondrial aconitase. Differential recognition between iso-IREs and iso-IRPs (iron regulatory proteins) regulates the translation or degradation of the IRE-containing mRNAs. IREs are hairpin loop structures with an internal loop/bulge or bulge that influence the binding of the iso-IRPs. The iso-IRPs have sequence homology to the aconitases and at least one IRP can be converted to an aconitase. Signals that target the iso-IRE/iso-IRP interactions in mRNA include environmental iron, O2, nitric oxide, H2O2, ascorbate, growth factors, and protein kinase C-dependent IRP phosphorylation. Iso-IRE structural specificity suggests a means of pharmacologically targeting mRNA function with chemicals such as Fe-bleomycin and other transition metal complexes that could be extended to other mRNAs with specific structures. With the iso-IRE/iso-IRP system, nature has evolved coordinated combinatorial control of iron and oxygen metabolism that may exemplify control of mRNAs in other metabolic pathways, viral reproduction, and oncogenesis.
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PMID:Targeting mRNA to regulate iron and oxygen metabolism. 1060 37

Toxic and carcinogenic free radical processes induced by drugs and other chemicals are probably modulated by the participation of available iron. To see whether endogenous iron was genetically variable in normal mice, the common strains C57BL/10ScSn, C57BL/6J, BALB/c, DBA/2, and SWR were examined for major differences in their hepatic non-heme iron contents. Levels in SWR mice were 3- to 5-fold higher than in the two C57BL strains, with intermediate levels in DBA/2 and BALB/c mice. Concentrations in kidney, lung, and especially spleen of SWR mice were also greater than those in C57BL mice. Non-denaturing PAGE of hepatic ferritin from all strains showed a major holoferritin band at approximately 600 kDa, with SWR mice having > 3-fold higher levels than C57BL strains. SDS PAGE showed a band of 22 kDa, mainly representing L-ferritin subunits. A trace of a subunit at 18 kDa was also detected in ferritin from SWR mice. The 18 kDa subunit and a 500 kDa holoferritin from which it originates were observed in all strains after parenteral iron overload, and there was no major variation in ferritin patterns. Although iron uptake studies showed no evidence for differential duodenal absorption between strains to explain the variation in basal iron levels, acquisition of absorbed iron by the liver was significantly higher in SWR mice than C57BL/6J. As with iron and ferritin contents, total iron regulatory protein (IRP-1) binding capacity for mRNA iron responsive element (IRE) and actual IRE/IRP binding in the liver were significantly greater in SWR than C57BL/6J mice. Cytosolic aconitase activity, representing unbound IRP-1, tended to be lower in the former strain. SWR mice were more susceptible than C57BL/10ScSn mice to the toxic action of diquat, which is thought to involve iron catalysis. If extrapolated to humans, the findings could suggest that some people might have the propensity for greater basal hepatic iron stores than others, which might make them more susceptible to iron-catalysed toxicity caused by oxidants.
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PMID:Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress. 1081 Apr 45

Manduca sexta IRP1 was cloned and sequenced. The deduced amino acid sequence of Manduca IRP1 shows high similarity to other IRP1 proteins. The Cys residues required as ligands for the iron sulfur cluster, as well as all residues necessary for aconitase activity are conserved in the insect protein. Purified recombinant Manduca IRP1 binds specifically to transcripts of the iron responsive element (IRE) of Manduca or human ferritin subunit mRNA. Binding activity of the recombinant protein was not influenced by the presence of beta-mercaptoethanol. However, IRP/IRE binding activity of cytoplasmic extracts from fat body was decreased by reducing agents in a dose-responsive manner. Fat body IRP1/IRE binding activity was reduced for Manduca sexta larvae injected with low doses of iron, while IRP1 mRNA and protein levels remained stable. At higher iron doses, binding activity increased and stabilized. Hemolymph ferritin levels showed an inverse relationship to IRP1/IRE binding activity. These data suggest that the Manduca IRP1 is likely involved in translational control of ferritin synthesis in a manner similar to that found in vertebrates. However, factors other than iron can influence IRP/IRE interaction and hemolymph ferritin levels in insects.
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PMID:Manduca sexta IRP1: molecular characterization and in vivo response to iron. 1171 72

Changes in iron homeostasis have been implicated in cardiotoxicity induced by the anticancer anthracycline doxorubicin (DOX). Certain products of DOX metabolism, like the secondary alcohol doxorubicinol (DOXol) or reactive oxygen species (ROS), may contribute to cardiotoxicity by inactivating iron regulatory proteins (IRP) that modulate the fate of mRNAs for transferrin receptor and ferritin. It is important to know whether DOXol and ROS act by independent or combined mechanisms. Therefore, we monitored IRP activities in H9c2 rat embryo cardiomyocytes exposed to DOX or to analogues which were selected to achieve a higher formation of secondary alcohol metabolite (daunorubicin), a concomitant increase of alcohol metabolite and decrease of ROS (5-iminodaunorubicin), or a defective conversion to alcohol metabolite (mitoxantrone). On the basis of such multiple comparisons, we characterized that DOXol was able to remove iron from the catalytic Fe-S cluster of cytoplasmic aconitase, making this enzyme switch to the cluster-free IRP-1. ROS were not involved in this step, but they converted the IRP-1 produced by DOXol into a null protein which did not bind to mRNA, nor was it able to switch back to aconitase. DOX was also shown to inactivate IRP-2, which does not assemble or disassemble a Fe-S cluster. Comparisons between DOX and the analogues revealed that IRP-2 was inactivated only by ROS. Thus, DOX can inactivate both IRP through a sequential action of DOXol and ROS on IRP-1 or an independent action of ROS on IRP-2. This information serves guidelines for designing anthracyclines that spare iron homeostasis and induce less severe cardiotoxicity.
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PMID:Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. 1173 22

Iron regulatory proteins (IRPs) control the synthesis of various proteins at the translational level by binding to iron responsive elements (IREs) in the mRNAs. Iron, infection, and stress can alter IRP/IRE binding activity. Insect messenger RNAs for ferritin and succinate dehydrogenase subunit b have IREs that are active translational control sites. We have cloned and sequenced cDNAs encoding proteins from the IRP1 family for the mosquitoes, Aedes aegypti and Anopheles gambiae. Both deduced amino acid sequences show substantial similarity to human IRP1 and Drosophila IRP1A and IRP1B, and all of the residues thought to be involved in aconitase activity and iron-sulfur cluster formation are conserved. Recombinant A. aegypti IRP1 binds to transcripts of the IREs of mosquito or human ferritin subunit mRNAs. No significant change in A. gambiae IRP1 messenger RNA could be detected during the various developmental stages of the life cycle, following iron loading by blood feeding, or after bacterial or parasitic infections. These data suggest that there is no change in gene transcription. Furthermore, bacterial challenge of A. gambiae cells did not change IRP1 protein levels. In contrast, IRP1 binding activity for the IRE was elevated following immune induction. These data show that changes in IRP1/IRE binding activity occur as part of the insect immune response.
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PMID:Cloning and molecular characterization of two mosquito iron regulatory proteins. 1189 Nov 34

Iron regulatory proteins (IRPs) control iron metabolism by specifically interacting with iron-responsive elements (IREs) on mRNAs. Nitric oxide (NO) converts IRP-1 from a [4Fe-4S] aconitase to a trans-regulatory protein through Fe-S cluster disassembly. Here, we have focused on the fate of IRE binding IRP1 from murine macrophages when NO flux stops. We show that virtually all IRP-1 molecules from NO-producing cells dissociated from IRE and recovered aconitase activity after re-assembling a [4Fe-4S] cluster in vitro. The reverse change in IRP-1 activities also occurred in intact cells no longer exposed to NO and did not require de novo protein synthesis. Likewise, inhibition of mitochondrial aconitase via NO-induced Fe-S cluster disassembly was also reversed independently of protein translation after NO removal. Our results provide the first evidence of Fe-S cluster repair of NO-modified aconitases in mammalian cells. Moreover, we show that reverse change in IRP-1 activities and repair of mitochondrial aconitase activity depended on energized mitochondria. Finally, we demonstrate that IRP-1 activation by NO was accompanied by both a drastic decrease in ferritin levels and an increase in transferrin receptor mRNA levels. However, although ferritin expression was recovered upon IRP-1-IRE dissociation, expression of transferrin receptor mRNA continued to rise for several hours after stopping NO flux.
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PMID:Recycling of RNA binding iron regulatory protein 1 into an aconitase after nitric oxide removal depends on mitochondrial ATP. 1203 60

Nitric oxide (NO) is a signaling molecule that plays a critical role in the activation of innate immune and inflammatory responses in animals. During the last few years, NO has also been detected in several plant species and the increasing number of reports on its function in plants have implicated NO as an important effector of growth, development and defense. Analogously to animals, NO has been recently shown to inhibit tobacco aconitase. This suggests that NO may elevate free iron levels in the cells by converting tobacco cytoplasmic aconitase into a mRNA binding protein that negatively regulates accumulation of ferritin. We investigated the possible role of NO as a regulator of ferritin levels in Arabidopsis and found that the NO-donor sodium nitroprusside (SNP) induces accumulation of ferritin both at mRNA and protein level. Iron is not necessary for this NO-mediated ferritin transcript accumulation, since SNP is still able to induce the accumulation of ferritin transcript in Arabidopsis suspension cultures pre-treated with the iron chelants DFO or ferrozine. However, NO is required for iron-induced ferritin accumulation, as the NO scavenger CPTIO prevents ferritin transcript accumulation in Arabidopsis suspension cultures treated with iron. The pathway is ser/thr phosphatase-dependent and necessitates protein synthesis; furthermore, NO mediates ferritin regulation through the IDRS sequence of the Atfer1 promoter responsible for transcriptional repression under low iron supply. NO, by acting downstream of iron in the induction of ferritin transcript accumulation is therefore a key signaling molecule for regulation of iron homeostasis in plants.
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PMID:Nitric oxide mediates iron-induced ferritin accumulation in Arabidopsis. 1204 27

Iron acquisition is a fundamental requirement for many aspects of life, but excess iron may result in formation of free radicals that damage cellular constituents. For this reason, the amount of iron within the cell is carefully regulated in order to provide an adequate level of a micronutrient while preventing its accumulation and toxicity. A major mechanism for the regulation of iron homeostasis relies on the post-transcriptional control of ferritin and transferrin receptor mRNAs, which are recognized by two cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) that modulate their translation and stability, respectively. IRP-1 can function as a mRNA binding protein or as an aconitase, depending on whether it disassembles or assembles an iron-sulfur cluster in response to iron deficiency or abundancy, respectively. IRP-2 is structurally and functionally similar to IRP-1, but does not assemble a cluster nor exhibits aconitase activity. Here we briefly review the role of IRP in iron-mediated damage induced by oxygen radicals, nitrogen-centered reactive species, and xenobiotics of pharmacological and clinical interest.
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PMID:The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. 1205 61

Iron regulatory protein-1 (IRP-1) is a cytosolic RNA-binding protein that is a regulator of iron homeostasis in mammalian cells. IRP-1 binds to RNA structures, known as iron-responsive elements, located in the untranslated regions of specific mRNAs, and it regulates the translation or stability of these mRNAs. Iron regulates IRP-1 activity by converting it from an RNA-binding apoprotein into a [4Fe-4S] cluster protein exhibiting aconitase activity. IRP-1 is widely found in prokaryotes and eukaryotes. Here, we report the biochemical characterization and regulation of an IRP-1 homolog in Caenorhabditis elegans (GEI-22/ACO-1). GEI-22/ACO-1 is expressed in the cytosol of cells of the hypodermis and the intestine. Like mammalian IRP-1/aconitases, GEI-22/ACO-1 exhibits aconitase activity and is post-translationally regulated by iron. Although GEI-22/ACO-1 shares striking resemblance to mammalian IRP-1, it fails to bind RNA. This is consistent with the lack of iron-responsive elements in the C. elegans ferritin genes, ftn-1 and ftn-2. While mammalian ferritin H and L mRNAs are translationally regulated by iron, the amounts of C. elegans ftn-1 and ftn-2 mRNAs are increased by iron and decreased by iron chelation. Excess iron did not significantly alter worm development but did shorten their life span. These studies indicated that iron homeostasis in C. elegans shares some similarities with those of vertebrates.
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PMID:Cytosolic aconitase and ferritin are regulated by iron in Caenorhabditis elegans. 1243 12


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