Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs.

Leibold, Elizabeth A.; Munro, Hamish N.

doi:10.1073/pnas.85.7.2171

Cited by 652 publications

(318 citation statements)

References 27 publications

(16 reference statements)

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“…Further investigations of the 3Ј-untranslated regions of rGSTA2 and M1 mRNAs should inform on the presence of sequences possibly involved in the regulation of these transcripts by IL-1. Other studies reported a posttranscriptional down-regulation of ferritin and C-reactive protein by IL-1, as a consequence of reduced mRNA translation (36,37).…”

Section: Figmentioning

confidence: 99%

Modulation of Glutathione S-Transferase Subunits A2, M1, and P1 Expression by Interleukin-1β in Rat Hepatocytes in Primary Culture

Mahéo¹,

Antras-Ferry

Morel

et al. 1997

Journal of Biological Chemistry

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The influence of various cytokines on the expression of glutathione S-transferases (GSTs) was investigated in rat hepatocytes in primary culture. Only treatment of hepatocytes with interleukin-1␤ (IL-1) was effective, resulting in a marked decrease in GSTs. Steady-state mRNA levels of rGSTA2 and M1 were strongly downregulated by IL-1 in a dose-dependent manner after a 24-h exposure while rGSTP1 mRNA level was increased by a 48-h treatment. Similar effects of IL-1 were observed at the protein level. The response to IL-1 appeared to be specific for each subunit within GST gene families. In addition, IL-1 strongly suppressed the induction of rGSTA2 by 3-methylcholanthrene, oltipraz (a synthetic derivative of 1,2-dithiole-3-thione), and phenobarbital and that of rGSTM1 by oltipraz and phenobarbital, whereas it was ineffective on rGSTP1 induction by these compounds. Using in vitro nuclear run-on transcription assay and Northern blot analysis of ␣-amanitin-treated cells, IL-1-mediated rGSTM1 mRNA decrease was found to result from mRNA destabilization. These results provide the first demonstration that IL-1 regulates some major GST subunits in hepatocytes by a post-transcriptional mechanism.

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Section: Figmentioning

confidence: 99%

Modulation of Glutathione S-Transferase Subunits A2, M1, and P1 Expression by Interleukin-1β in Rat Hepatocytes in Primary Culture

Mahéo¹,

Antras-Ferry

Morel

et al. 1997

Journal of Biological Chemistry

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“…For investigation of IRP binding activity, a 32 P-labeled IRE probe was prepared by an in vitro transcription procedure exactly as described [63] and the analysis of RNA/protein complexes was carried out by nondenaturing gel electrophoresis. The 2-mercaptoethanol (2%) was used for in vitro stimulation of IRP1-binding activity to ensure for equal loading of protein extracts [64]. …”

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confidence: 99%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

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In stimulating effector functions of mononuclear phagocytes, IFN-c is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-c is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-c on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-c caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-c exerting a super-inducing effect. This observed regulatory impact of IFN-c reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-a production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-c concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. IntroductionHost defense against intracellular microbes such as salmonellae or mycobacteria strongly depends on cell-mediated immunity, a major component of which is characterized by interactions between Th1 cells and macrophages [1]. By secreting Th1 cytokines, particularly IFN-c, antigen-specific Th1 cells activate a plethora of microbicidal mechanisms in infected macrophages. Specifically, in mononuclear phagocytes infected with Salmonella enterica serovar typhimurium (S. typhimurium), IFN-c promotes the internalization of bacteria and stimulates their elimination by various mechanisms including reactive oxygen and nitrogen species (ROS and RNS), generated via NADPH phagocyte oxidase and iNOS, respectively [2][3][4][5]. In Salmonella-infected mice, treatment with recombinant IFN-c increases host survival and decreases bacterial numbers in liver and spleen [6]. Conversely, neutralization of murine IFN-c functions with specific antibodies results in reduced host survival and increased bacterial counts [7]. Eur. J. Immunol. 2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virule...

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“…An increase in the delivery of iron to cells therefore serves as a powerful stimulus for ferritin synthesis. It is now established that iron-dependent ferritin and transferrin receptor gene expression is regulated by the binding of two iron regulatory proteins (IRPs), IRP-1 and IRP-2, to sequences termed iron-responsive elements (IREs) present at the 5Ј-untranslated region of ferritin mRNA and the 3Ј-untranslated region of Tf receptor mRNA (13)(14)(15)(16)(17). In irondepleted cells, IRPs bind with high affinity to the IREs, resulting in suppression of ferritin mRNA translation and stabilization of Tf receptor mRNA (increased Tf receptor synthesis).…”

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confidence: 99%

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

Chitambar

Wereley

1997

Journal of Biological Chemistry

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The mechanism of drug resistance to gallium nitrate is not known. Since gallium can be incorporated into ferritin, an iron storage protein that protects cells from iron toxicity, we investigated whether ferritin expression was altered in gallium-resistant (R) CCRF-CEM cells. We found that the ferritin content of R cells was decreased, while heavy chain ferritin mRNA levels and iron regulatory protein-1 (IRP-1) RNA binding activity were increased. IRP-1 protein levels were similar in gallium-sensitive (S) and R cells, indicating that R cells contain a greater proportion of IRP-1 in a high affinity mRNA binding state. 59 Fe uptake and transferrin receptor expression were decreased in R cells. In both S and R cells, gallium inhibited cellular 59 Fe uptake, increased ferritin mRNA and protein, and decreased IRP-1 binding activity. Gallium uptake by R cells was markedly diminished; however, the sensitivity of R cells to gallium could be restored by increasing their uptake of gallium with excess transferrin. Our results suggest that R cells have developed resistance to gallium by down-regulating their uptake of gallium. In parallel, iron uptake by R cells is also decreased, leading to changes in iron homeostasis. Furthermore, since gallium has divergent effects on iron uptake and ferritin synthesis, its action may also include a direct effect on ferritin mRNA induction and IRP-1 activity.Gallium nitrate, a group IIIa metal salt with antineoplastic activity (1), is currently undergoing evaluation as a chemotherapeutic agent. A number of clinical studies have shown gallium to be effective in the treatment of lymphoma and bladder cancer (2-4). Although gallium is in clinical use, information regarding its action at the cellular and molecular levels is largely incomplete. It has been known for some time that gallium resembles iron in certain respects. Gallium binds avidly to the iron transport protein Tf 1 (5) and is incorporated into cells by Tf receptor-dependent and -independent transport systems (6 -8). Furthermore, we have shown that gallium inhibits the growth of several leukemic cell lines by inhibiting cellular iron uptake and by blocking the activity of ribonucleotide reductase (9 -11).Iron taken up by cells is stored in ferritin, a high molecular weight protein composed of 24 subunits of H and L chains (12). Ferritin sequesters excess intracellular iron and protects cells from the toxicity of iron overload. An increase in the delivery of iron to cells therefore serves as a powerful stimulus for ferritin synthesis. It is now established that iron-dependent ferritin and transferrin receptor gene expression is regulated by the binding of two iron regulatory proteins (IRPs), IRP-1 and IRP-2, to sequences termed iron-responsive elements (IREs) present at the 5Ј-untranslated region of ferritin mRNA and the 3Ј-untranslated region of Tf receptor mRNA (13-17). In irondepleted cells, IRPs bind with high affinity to the IREs, resulting in suppression of ferritin mRNA translation and stabilization of Tf receptor mRNA (incr...

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Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs.

Cited by 652 publications

References 27 publications

Modulation of Glutathione S-Transferase Subunits A2, M1, and P1 Expression by Interleukin-1β in Rat Hepatocytes in Primary Culture

Modulation of Glutathione S-Transferase Subunits A2, M1, and P1 Expression by Interleukin-1β in Rat Hepatocytes in Primary Culture

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

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