Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9UIJ5 (Rec)
 58,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute-phase protein alpha 1-antitrypsin (alpha 1-AT) has been shown to inhibit the binding of transferrin to its cell-surface receptor. Here we demonstrate that in human erythroleukaemic cells (K562) alpha 1-AT enhances the binding affinity of iron-regulatory protein (IRP), the central regulator of cellular iron metabolism, to iron-responsive elements. Activation of IRP by alpha 1-AT is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and enhanced cell-surface expression of transferrin-binding sites, whereas ferritin production is decreased, although ferritin mRNA levels remain unchanged. In agreement with the well-established mechanism of cellular iron regulation, alpha 1-AT seems to modulate trf-rec and ferritin expression primarily post-transcriptionally/translationally by influencing IRP activity. In contrast, alpha 1-AT produces only minor changes in IRP activity, and subsequently in trf-rec expression and ferritin synthesis in THP-1 cells. Moreover the effects of alpha 1-AT on iron homeostasis in K562 cannot be overcome by the addition of iron salts, whereas concomitant treatment of THP-1 with iron and alpha 1-AT results in the same metabolic changes as the addition of iron alone. Because alpha 1-AT blocks transferrin binding on K562 as well as on THP-1 cells, it is suggested, on the basis of the results presented here, (1) that erythroid and monocytic cells might differ in their dependence on transferrin-mediated iron supply and (2) that THP-1 might be able to acquire iron by a transferrin-independent iron uptake system. alpha 1-AT might therefore be involved in the diversion of iron traffic between various cellular compartments under inflammatory conditions.
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PMID:Divergent effects of alpha 1-antitrypsin on the regulation of iron metabolism in human erythroleukaemic (K562) and myelomonocytic (THP-1) cells. 892 Sep 96

Erythropoietin (Epo) is the central regulator of red blood cell production and acts primarily by inducing proliferation and differentiation of erythroid progenitor cells. Because a sufficient supply of iron is a prerequisite for erythroid proliferation and hemoglobin synthesis, we have investigated whether Epo can regulate cellular iron metabolism. We present here a novel biologic function of Epo, namely as a potential modulator of cellular iron homeostasis. We show that, in human (K562) and murine erythroleukemic cells (MEL), Epo enhances the binding affinity of iron-regulatory protein (IRP)-1, the central regulator of cellular iron metabolism, to specific RNA stem-loop structures, known as iron-responsive elements (IREs). Activation of IRP-1 by Epo is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and MEL, enhanced cell surface expression of trf-recs, and increased uptake of iron into cells. These findings are in agreement with the well-established mechanism whereby high-affinity binding of IRPs to IREs stabilizes trf-rec mRNA by protecting it from degradation by a specific RNase. The effects of Epo on IRE-binding of IRPs were not observed in human myelomonocytic cells (THP-1), which indicates that this response to Epo is not a general mechanism observed in all cells but is likely to be erythroid-specific. Our results provide evidence for a direct functional connection between Epo biology and iron metabolism by which Epo increases iron uptake into erythroid progenitor cells via posttranscriptional induction of trf-rec expression. Our data suggest that sequential administration of Epo and iron might improve the response to Epo therapy in some anemias.
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PMID:Regulation of cellular iron metabolism by erythropoietin: activation of iron-regulatory protein and upregulation of transferrin receptor expression in erythroid cells. 900 72

Dexrazoxane (ICRF-187) has recently been demonstrated to reduce cardiac toxicity induced by chemotherapy with anthracyclines, although the reason for this phenomenon has remained obscure thus far. In order to investigate whether ICRF-187 might exert its effects by modulating iron metabolism, we studied the drug's potential to influence the maintenance of iron homeostasis in two human cell lines. We demonstrate that ICRF-187 enhanced the binding affinity of iron regulatory protein (IRP), the central regulatory factor for posttranscriptional iron regulation, to RNA stem loop structures, called iron responsive elements (IRE), in THP-1 myelomonocytic as well as K562 erythroleukemic cells. Increased IRE/IRP interaction was paralleled by an elevation of transferrin receptor (trf-rec) mRNA levels which, according to the well-established mechanism of posttranscriptional iron regulation, was likely due to stabilisation of trf-rec mRNA by IRP. Subsequently, ICRF-187 treatment of cells increased trf-rec surface expression and enhanced cellular iron uptake. All these events, i.e. IRP activation, stabilisation of trf-rec mRNA and increased surface expression of the protein in response to ICRF-187, follow a dose-response relationship. Increased cellular uptake and sequestration of iron in response to ICRF-187 may contribute to the protective activity of ICRF-187 by reducing the iron-anthracycline complex and iron-catalysed generation of hydroxyl radicals via the Haber-Weiss reaction.
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PMID:Modulation of transferrin receptor expression by dexrazoxane (ICRF-187) via activation of iron regulatory protein. 926 Aug 68

Iron plays a crucial role in the survival, differentiation, and myelin formation of oligodendrocyte lineages. However, the regulation mechanism of iron homeostasis in oligodendrocytes remains unclear. Recently, much research has focused on Ferroportin 1 (FPN1), an iron exporter protein. First, about 95% pure primary rat O-2A progenitor cells were obtained by shaking methods in our laboratory. The expression of FPN1 mRNA and protein in O-2A progenitor cells were determined by reverse transcription-PCR and western blot. In addition, the localization of FPN1 at the cell membrane, in the cytoplasm and in processes was assayed by double-labeling immunofluorescence. A time-dependent increase of iron efflux from O-2A progenitor cells was confirmed by the calcein-indicated iron efflux assay. However, the same cells treated with FPN1 antibody showed no obvious change in iron release. For further confirmation, overexpression of FPN1 in O-2A progenitor cells was transduced with lentivirus. The release of iron in O-2A progenitor cells was dramatically increased by the overexpressed FPN1 when compared with that of the control group. Both ferritin (Ft) and transferrin receptor (TfR) are routinely used as indicators of labile iron pool. Cells pretreated with FPN1 antibody upregulated Ft and downregulated TfR protein level, while the opposite results occurred in the FPN1 overexpressing cells. Determination of Ft and TfR indirectly indicated that FPN1 might contribute to iron release from O-2A progenitor cells. We suggested that expression of FPN1 in O-2A progenitor cells might play a critical role in iron efflux from these cells.
Anat Rec (Hoboken) 2013 Jan
PMID:Expression and function of ferroportin 1 in O-2A progenitor cells. 2311 87