Role of Ferritin in the Control of the Labile Iron Pool in Murine Erythroleukemia Cells

Picard, Virginie; Epsztejn, Silvina; Santambrogio, Paolo; Cabantchik, Z. Ioav; Beaumont, Carole

doi:10.1074/jbc.273.25.15382

Cited by 122 publications

(91 citation statements)

References 29 publications

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“…Additionally, mimosine does not inhibit the activity of the E. coli vitamin B12-dependent methionine synthase in vitro. 2 These results show that the effect of mimosine on folate metabolism is independent of MS activity.…”

Section: Mimosine Targets Tumor Cell Lines With Specificity-sev-mentioning

confidence: 53%

“…Cells were lysed with 1 ml of 50 mM potassium phosphate, pH 7.2, containing 0.1% Triton X-100. SHMT activity was determined in the crude cell extracts by measuring the rate of exchange of the pro-2S proton of [2][3] H]glycine, as described previously (20). This assay measures both mitochondrial and cytoplasmic SHMT activity.…”

Section: Figmentioning

confidence: 99%

“…Many of these responses are mediated through the iron regulatory protein, which can bind with specificity to certain mRNA species and regulate translation (1). The concentration of cellular regulatory iron is decreased by iron deficiency or by elevated expression of heavy chain ferritin, a protein that sequesters intracellular iron (2,3). Sequestration of intracellular iron by chelators, including DFO, 1 has been commonly used to trigger physiological changes associated with iron deficiency.…”

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confidence: 99%

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Mimosine Is a Cell-specific Antagonist of Folate Metabolism

Oppenheim

Nasrallah

Mastri

et al. 2000

Journal of Biological Chemistry

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Iron deficiency and iron chelators are known to alter folate metabolism in mammals, but the underlying biochemical mechanisms have not been established. Although many studies have demonstrated that the iron chelators mimosine and deferoxamine inhibit DNA replication in mammalian cells, their mechanism of action remains controversial. The effects of mimosine on folate metabolism were investigated in human MCF-7 cells and SH-SY5Y neuroblastoma. Our findings indicate that mimosine is a folate antagonist and that its effects are cell-specific. MCF-7 cells cultured in the presence of 350 M mimosine were growth-arrested, whereas mimosine had no effect on SH-SY5Y cell proliferation. Mimosine altered the distribution of folate cofactor forms in MCF-7 cells, indicating that mimosine targets folate metabolism. However, mimosine does not influence folate metabolism in SH-SY5Y neuroblastoma. The effect of mimosine on folate metabolism is associated with decreased cytoplasmic serine hydroxymethyltransferase (cSHMT) expression in MCF-7 cells but not in SH-SY5Y cells. MCF-7 cells exposed to mimosine for 24 h have a 95% reduction in cSHMT protein, and cSHMT promoter activity is reduced over 95%. Transcription of the cSHMT gene is also inhibited by deferoxamine in MCF-7 cells, indicating that mimosine inhibits cSHMT transcription by chelating iron. Analyses of mimosine-resistant MCF-7 cell lines demonstrate that although the effect of mimosine on cell cycle is independent of its effects on cSHMT expression, it inhibits both processes through a common regulatory mechanism.There are several well characterized cellular responses that are triggered following decreases in the regulatory, non-ferritin-bound iron pool. Many of these responses are mediated through the iron regulatory protein, which can bind with specificity to certain mRNA species and regulate translation (1). The concentration of cellular regulatory iron is decreased by iron deficiency or by elevated expression of heavy chain ferritin, a protein that sequesters intracellular iron (2, 3). Sequestration of intracellular iron by chelators, including DFO, 1 has been commonly used to trigger physiological changes associated with iron deficiency. The influence of iron deficiencies, both induced and naturally occurring, on folate metabolism has been well documented in cell culture models, animal models, and humans. Iron deficiency can result in morphological alterations in granulocytes similar to folate deficiency (4), and iron deficiency has been demonstrated to impair folate utilization in some but not all tissues (5). In addition, maternal iron deficiency decreases secretion of folate into milk (6, 7) without decreasing maternal serum or red blood cell folate levels in rats. However, the biochemical mechanisms underlying the influence of iron deficiency on folate metabolism have not been established (6).Mimosine, a plant amino acid and tyrosine analog ( Fig. 1), is a toxin that chelates iron and inhibits mammalian DNA replication. Mimosine is known to block DNA replication...

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Section: Mimosine Targets Tumor Cell Lines With Specificity-sev-mentioning

confidence: 53%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

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Mimosine Is a Cell-specific Antagonist of Folate Metabolism

Oppenheim

Nasrallah

Mastri

et al. 2000

Journal of Biological Chemistry

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“…More instructive was the production of mouse erythroleukemic (MEL) cells lines stably transfected with mouse ferritin H-chain cDNA in which the IRE was inactivated and H-ferritin was constitutively up-regulated (21). The cells accumulated H-ferritin up to 5-fold over background and were found to be iron starving and to have significant reduction of labile iron pool; in addition they showed reduced heme and hemoglobin synthesis, were more resistant to oxidative damage, and had multidrug resistance properties (21)(22)(23). The results indicate that the H-subunit has active roles in regulating iron-related metabolic processes, whereas the L-chain seem inactive.…”

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confidence: 74%

“…23. Cells (2 ϫ 10 6 ) were incubated with 0.250 M calcein-AM (Molecular Probes) for 15 min at 37°C in bicarbonate free medium containing 1 mg/ml bovine serum albumin and 20 mM HEPES, pH 7.3.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Wild Type and Mutated Human Ferritin H-chain in HeLa Cells

Cozzi¹,

Corsi²,

Levi³

et al. 2000

Journal of Biological Chemistry

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229

209

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Transfectant HeLa cells were generated that expressed human ferritin H-chain wild type and an Hchain mutant with inactivated ferroxidase activity under the control of the tetracycline-responsive promoter (Tet-off). The clones accumulated exogenous ferritins up to levels 14 -16-fold over background, half of which were as H-chain homopolymers. This had no evident effect in the mutant ferritin clone, whereas it induced an irondeficient phenotype in the H-ferritin wild type clone, manifested by ϳ5-fold increase of IRPs activity, ϳ2.5-fold increase of transferrin receptor, ϳ1.8-fold increase in iron-transferrin iron uptake, and ϳ50% reduction of labile iron pool. Overexpression of the H-ferritin, but not of the mutant ferritin, strongly reduced cell growth and increased resistance to H 2 O 2 toxicity, effects that were reverted by prolonged incubation in iron-supplemented medium. The results show that in HeLa cells H-ferritin regulates the metabolic iron pool with a mechanism dependent on the functionality of the ferroxidase centers, and this affects, in opposite directions, cellular growth and resistance to oxidative damage. This, and the finding that also in vivo H-chain homopolymers are much less efficient than the H/L heteropolymers in taking up iron, indicate that functional activity of H-ferritin in HeLa cells is that predicted from the in vitro data.

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Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

Doguer

Collins

2018

Comprehensive Physiology

121

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Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HIF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states. © 2018 American Physiological Society. Compr Physiol 8:1433-1461, 2018.

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Role of Ferritin in the Control of the Labile Iron Pool in Murine Erythroleukemia Cells

Cited by 122 publications

References 29 publications

Mimosine Is a Cell-specific Antagonist of Folate Metabolism

Mimosine Is a Cell-specific Antagonist of Folate Metabolism

Overexpression of Wild Type and Mutated Human Ferritin H-chain in HeLa Cells

Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

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