Oxidative Stress Leads to a Rapid Alteration of Transferrin Receptor Intravesicular Trafficking

Malorni, Walter; Testa, Ugo; Rainaldi, Gabriella; Tritarelli, Elena; Peschle, Cesare

doi:10.1006/excr.1998.4020

Cited by 51 publications

(25 citation statements)

References 56 publications

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“…These combined observations indicate that exposure to Mb manifests as a subtle cellular effect with an absence of any general cell cytotoxicity. It follows that this demonstrable oxidative stress may inhibit receptor-mediated endocytosis as reported previously [45] . Alternately, the release and subsequent uptake of free haem from Mb combined with haem catabolism through enhanced HO activity may perturb the intracellular pools of labile iron and provide feedback inhibition of transferrin uptake [46] .…”

Section: Enhanced Oxidative Stress In Mdck II Cells In Response To Mbmentioning

confidence: 65%

Myoglobin Induces Oxidative Stress and Decreases Endocytosis and Monolayer Permissiveness in Cultured Kidney Epithelial Cells without Affecting Viability

Parry

Ellis²,

Li³

et al. 2008

Kidney Blood Press Res

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Background: Muscle degradation caused by severe burn releases myoglobin (Mb), which accumulates in the kidney (termed myoglobinuria). Mb is a pro-oxidant. Aim: To demonstrate that Mb promotes oxidative stress and dysfunction in cultured Madin-Darby canine kidney type II (MDCK II) cells. Methods: The glutathione redox ratio was used to monitor oxidative stress. Regulation of antioxidant response genes was determined with RT-PCR. Propidium iodide and annexin V staining were markers of necrosis and apoptosis, respectively. Mitochondrial function was assessed by monitoring mitochondrial depolarisation. Endocytosis was determined with immune fluorescence microscopy, and monolayer permeability was monitored with labelled inulin. Results: Kidney epithelial cells exposed to (0–100 µM) Mb showed a dose-dependent decrease in the glutathione redox ratio indicative of enhanced oxidative stress. In parallel, the expression of antioxidant genes for superoxide dismutase (SOD)-1/2, inducible haemoxygenase (HO-1) and catalase (CAT) increased in MDCK II cells, coupled with increases in corresponding activity. Notably, apoptosis and necrosis remained unaffected. However, transferrin endocytosis and monolayer permeability decreased significantly, while clathrin distribution and mitochondrial function were unaffected. Conclusion: Low concentrations of Mb promote oxidative stress in kidney epithelial cells that manifest as subtle changes to function without decreasing viability. Whether this impairs kidney function in burns patients is not clear.

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Section: Enhanced Oxidative Stress In Mdck II Cells In Response To Mbmentioning

confidence: 65%

Myoglobin Induces Oxidative Stress and Decreases Endocytosis and Monolayer Permissiveness in Cultured Kidney Epithelial Cells without Affecting Viability

Parry

Ellis²,

Li³

et al. 2008

Kidney Blood Press Res

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“…Unbound ligand was removed by centrifugation of the cells through a density cushion, as described previously. 35 After incubation, 200-L aliquots of the cell suspension were layered over 150 L dibutyl phthalate and dinonyl phtalate (Merck, Darmstadt, Germany) mixture, to a final density to 1.0125, in 400-L plastic microcentrifuge tubes and were centrifuged in an Eppendorf (Milan, Italy) microcentrifuge (10 000g for 2 minutes). At the end of centrifugation, the supernatant and most of the dibutyl phtalate cushion were aspirated.…”

Section: Il-3 Binding and Internalization Assaysmentioning

confidence: 99%

Elevated expression of IL-3Rα in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis

Testa

Riccioni

Militi

et al. 2002

Blood

Self Cite

292

239

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We have investigated the expression of interleukin-3 receptor ␣ (IL-3R␣) chain in primary blasts from 79 patients with acute myeloid leukemia (AML), 25 patients with B-acute lymphoid leukemia (B-ALL), and 7 patients with T-acute lymphoid leukemia (T-ALL) to evaluate a linkage between the expression of this receptor chain, blast proliferative status, and disease prognosis. Although IL-3R␣ chain was scarcely expressed in most patients with T-ALL, it was overexpressed in 40% and 45% of patients with B-ALL and AML, respectively, compared with the levels observed in normal CD34 ؉ progenitors. The biological and clinical significance of this overexpression pattern was investigated in AML. At the biological level, elevated IL-3R␣ expression was associated with peculiar properties of leukemic blasts, specifically in 3 areas. First, in all patients the blasts expressing elevated IL-3R␣ levels exhibited higher cycling activity and increased resistance to apoptosis triggered by growth factor deprivation. Second, spontaneous signal transducer and activator of transcription 5 (Stat5) phosphorylation was observed in 13% of AML patients, all pertaining to the group of patients exhibiting high IL-3R␣ expression. Third, following IL-3 treatment, Stat5 was activated at higher levels in blasts with elevated IL-3R␣ expression. At the clinical level, a significant correlation was observed between the level of IL-3R␣ expression and the number of leukemic blasts at diagnosis, and patients exhibiting elevated IL-3R␣ levels had a lower complete remission rate and survival duration than those showing normal IL-3R␣ levels. These findings suggest that in AML, deregulated expression of IL-3R␣ may contribute to the proliferative advantage of the leukemic blasts and, hence, to a poor prognosis. IntroductionBlood cells are derived from a small number of pluripotent hemopoietic stem cells (HSCs) endowed with the capacity to self-renew and to differentiate into hemopoietic progenitor cells (HPCs) progressively committed to proceed along one of the maturation pathways. 1 Survival, growth, and differentiation of HPCs are, at least in part, regulated by a network of hematopoietic growth factors (HGFs) called colony-stimulating factors (CSFs) or interleukins (ILs).Acute leukemias are characterized by an arrest of cell maturation and the accumulation of undifferentiated cells in marrow, blood, and other tissues. 2 As observed in normal hematopoiesis, most leukemic cells descend from a relatively small pool of progenitor cells with high proliferative activity. In line with this hypothesis, recent studies have shown that acute myeloid leukemia (AML) cells with the membrane phenotype CD34 ϩ Thy-1 Ϫ , 3 CD34 ϩ CD38 Ϫ , 4 or CD34 ϩ CD71 Ϫ HLA-DR Ϫ5 are capable of engrafting immunodeficient mice.Acute leukemia cells have usually retained responsiveness to HGF stimulation in the promotion of cell survival and cell proliferation; however, leukemic cells show little maturation under stimulation with HGFs. 6 More particularly, recombinant IL-3 and granulocyte...

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“…Previous studies in human hematopoietic K562 and HL-60 cells showed that oxidative stress (either in the form of menadione or extracellular H 2 O 2 ) results in a rapid (within 30 min) redistribution of TfR in intracellular compartments without alterations in TfR levels (35,50). These results appear to be IRP1-independent and are in contrast to the stimulatory effects of H 2 O 2 on the synthesis, accumulation, cell surface expression, and Tf binding activity of TfR observed in B6 cells (Figs.…”

Section: H 2 O 2 Leads To Increased Expression Of Functional Tfr On Tmentioning

confidence: 99%

“…The fraction of TfR expressed on the cell surface is crucial for Tf binding. In a previous report it was shown that H 2 O 2 negatively affects the size of this fraction, at least in human hematopoietic K562 and HL-60 cells (35). In light of these findings, we analyzed relative changes in cell surface expression of TfR in mouse B6 fibroblasts by means of FACS, using FITC-conjugated TfR antibodies (Fig.…”

Section: H 2 O 2 -Mediated Reduction Of Ferritin Pool and Accumulatiomentioning

confidence: 99%

Modulation of Cellular Iron Metabolism by Hydrogen Peroxide

Caltagirone

Weiss

Pantopoulos

2001

Journal of Biological Chemistry

107

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Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs. The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H 2 O 2 that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 M H 2 O 2 for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H 2 O 2 induces a ϳ4-fold increase in TfR mRNA levels within 2-6 h, and subsequent accumulation of newly synthesized protein after 4 h. This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells. Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the Divalent Metal Transporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs. Finally, H 2 O 2 -treated cells display an increased capacity to sequester 59 Fe in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of 59 Fe intracellular distribution. Our data suggest that H 2 O 2 regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.To satisfy metabolic needs for iron, mammalian cells utilize transferrin (Tf), 1 the iron carrier in plasma. Cellular iron uptake involves binding of Tf to the cell-surface Tf receptor (TfR), followed by endocytosis. Within the acidified endosome, iron is released from the Tf-TfR complex and transported, most likely by the Divalent Metal Transporter DMT1, across the endosomal membrane to the cytosol, where it becomes bioavailable for the synthesis of iron proteins. Excess iron is stored in ferritin, a multisubunit protein consisting of H-and L-chains, that serves as the major intracellular iron storage device (reviewed in Refs. 1-3). Sequestration of iron in ferritin is viewed as a detoxification step to reduce the risk of iron-mediated cell damage, which is based on the capacity of iron to catalyze the generation of toxic oxygen radicals (4). Balanced iron homeostasis is critical for health, and both iron deficiency as well as iron overload are associated with severe disorders (5).At the cellular level, iron homeostasis is accomplished by the coordinate regulation of iron uptake and storage. The expression of TfR and ferritin is mainly controlled post-transcriptionally by iron regulatory proteins, IRP1 and IRP2. Under conditions of iron starvation, IRP1 and...

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Oxidative Stress Leads to a Rapid Alteration of Transferrin Receptor Intravesicular Trafficking

Cited by 51 publications

References 56 publications

Myoglobin Induces Oxidative Stress and Decreases Endocytosis and Monolayer Permissiveness in Cultured Kidney Epithelial Cells without Affecting Viability

Myoglobin Induces Oxidative Stress and Decreases Endocytosis and Monolayer Permissiveness in Cultured Kidney Epithelial Cells without Affecting Viability

Elevated expression of IL-3Rα in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis

Modulation of Cellular Iron Metabolism by Hydrogen Peroxide

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