Dysregulation of IRP1-Mediated Iron Metabolism Causes Gamma Ray-specific Radioresistance in Leukemia Cells

Haro, Kurtis J.; Sheth, Aneesh; Scheinberg, David A.

doi:10.1371/journal.pone.0048841

Cited by 17 publications

(11 citation statements)

References 34 publications

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“…Direct treatment with 0.8 mM H 2 O 2 for 24 h failed to induce any evident modification. Red blood cells have antioxidant defenses that catabolize H 2 O 2 (such as catalase and the glutathione complex), but the hydroxyl radicals produced by the Fenton reaction due to changes in iron content cannot be directly inactivated and lead to increased cellular damage [ 56 ]. Moreover, this effect shows that iron modulation of Na,K-ATPase activity is not necessarily a result of increased expression of the pump on the cell membrane; instead, the increase may be caused by a direct interaction between iron and the enzyme pump or by the modulation of cholesterol and phospholipid content.…”

Section: Discussionmentioning

confidence: 99%

Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

et al. 2015

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Iron is an essential chemical element for human life. However, in some pathological conditions, such as hereditary hemochromatosis type 1 (HH1), iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload interferes with the Na,K-ATPase activity of the plasma membrane by studying erythrocytes that were obtained from the whole blood of patients suffering from iron overload. Additionally, we treated erythrocytes of normal subjects with 0.8 mM H2O2 and 1 μM FeCl3 for 24 h. We then analyzed the lipid profile, lipid peroxidation and Na,K-ATPase activity of plasma membranes derived from these cells. Iron overload was more frequent in men (87.5%) than in women and was associated with an increase (446%) in lipid peroxidation, as indicated by the amount of the thiobarbituric acid reactive substances (TBARS) and an increase (327%) in the Na,K-ATPase activity in the plasma membrane of erythrocytes. Erythrocytes treated with 1 μM FeCl3 for 24 h showed an increase (132%) in the Na,K-ATPase activity but no change in the TBARS levels. Iron treatment also decreased the cholesterol and phospholipid content of the erythrocyte membranes and similar decreases were observed in iron overload patients. In contrast, erythrocytes treated with 0.8 mM H2O2 for 24 h showed no change in the measured parameters. These results indicate that erythrocytes from patients with iron overload exhibit higher Na,K-ATPase activity compared with normal subjects and that this effect is specifically associated with altered iron levels.

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Section: Discussionmentioning

confidence: 99%

Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

et al. 2015

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“…The down-regulation of Fbxl5 by IR depends on both the decrease in its mRNA and the destabilization of the protein mediated by the same hemerythrin domain that confers sensitivity to iron. 69 The mechanism linking IR with hemerythrin-dependent destabilization of Fbxl5 is still unknown, but it is likely that IR might indirectly reduce the iron levels required for hemerythrin stability 100 or modulate the levels of the ubiquitin ligase that targets Fbxl5. 101 Moreover, Fbxl5 is also downregulated by hypoxia 97 which can also contribute to the Snail1 stabilization observed in these conditions.…”

Section: Scf-fbxl5mentioning

confidence: 99%

Regulation of the protein stability of EMT transcription factors

Dı́az

Viñas-Castells

Herreros

2014

Cell Adhesion & Migration

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“…Increased cellular ferritin has been shown to decrease ROS accumulation and protect cells against oxidative stress [23,24], whereas a decrease in ferritin levels induced by TGF-β in AML-12 cells increased an intracellular labile iron pool and promoted ROS formation [25]. ROS levels were increased in IRP-1silenced LLC-PK1 cells compared with the corresponding negative siRNA controls (Fig.…”

Section: Glutathione Levels After Irp-1 Silencingmentioning

confidence: 94%

Iron-dependent turnover of IRP-1/c-aconitase in kidney cells

Liu

Templeton

2015

Metallomics

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The kidney plays an important role in iron homeostasis and actively reabsorbs citrate. The bifunctional iron-regulatory protein IRP-1 potentially regulates iron trafficking and participates in citrate metabolism as a cytosolic (c-) aconitase. We investigated the role of cellular iron status in determining the expression and dynamics of IRP-1 in two renal cell types, with the aim of identifying a role of the protein in cellular ROS levels, citrate metabolism and glutamate production. The effects of iron supplementation and chelation on IRP-1 protein and mRNA levels and protein turnover were compared in cultured primary rat mesangial cells and a porcine renal tubule cell line (LLC-PK1). Levels of ROS were measured in both cell types, and c-aconitase activity, glutamate, and glutathione were measured in LLC-PK1 cells, with and without IRP-1 silencing and in glutamine-supplemented or nominally glutamine-free medium. Iron supplementation decreased IRP-1 levels (e.g., approx. 40% in mesangial cells treated with 10 μg ml(-1) iron for 16 h) and increased ubiquitinated IRP-1 levels in both cells types, with iron chelation having the opposite effect. Although iron increased ROS levels (three-fold with 20 μg ml(-1) iron in mesangial cells and more modestly by about 30% with 50 μg ml(-1) in LLC-PK1 cells, both after 24 h), protein degradation was not ROS-dependent. In LLC-PK1 cells, 10 μg ml(-1) iron (24 h) increased both aconitase activity (30%) and secreted glutamate levels (65%). Silencing did not remove the glutamate response to iron but decreased the c-aconitase activity of the residual protein independent of iron loading (37% and 46% of control levels, without and with iron treatment, respectively). However, in glutamine-free medium, glutamate was still increased by iron, even in IRP-1-silenced cells, and did not correspond to c-aconitase. Silencing decreased the amount of ferritin measured in response to iron loading, decreased the affect of iron on total glutathione by 48%, and increased the response of ROS to iron loading by 38%. We conclude that iron increases turnover of IRP-1 in kidney cells, while increasing aconitase activity, suggesting that the apoprotein (aconitase-inactive) form is not exclusively responsible for turnover. Iron increases glutamate levels in tubule epithelial cells, but this appears to be independent of c-aconitase activity or the availability of extracellular glutamine. IRP-1 protein levels are not regulated by ROS, but IRP-1-dependent ferritin expression may decrease ROS and increase total glutathione levels, suggesting that ferritin levels are more important than citrate metabolism in protecting renal cells against iron.

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Dysregulation of IRP1-Mediated Iron Metabolism Causes Gamma Ray-specific Radioresistance in Leukemia Cells

Cited by 17 publications

References 34 publications

Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

Regulation of the protein stability of EMT transcription factors

Iron-dependent turnover of IRP-1/c-aconitase in kidney cells

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