Redox control of iron regulatory protein 2 stability

Hausmann, Anja; Lee, Julie; Pantopoulos, Kostas

doi:10.1016/j.febslet.2011.01.036

Cited by 28 publications

(23 citation statements)

References 37 publications

(84 reference statements)

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“…In these studies, the effects of hypoxia on binding of IRPs to IRE appear to be somewhat inconsistent or complex, or may be context-dependent including cell types and species, hypoxic oxygen percent, and duration and time points of hypoxic conditions (40–42). Subsequent studies demonstrated that the relative involvement of IRP1 and IRP2 in the IRP-IRE regulatory system was determined by tissue oxygen levels and cellular redox states (43,44), and hypoxia stabilized and activated IRP2 through destabilization of FBXL5 and SKP1-CUL1 ubiquitin ligase protein complex (45,46) while hypoxia decreased IRP1 binding to IRE (43,47). Despite the induction of ferritin H mRNA by cobalt chloride in K562 cells, we found that ferritin H protein expression was strongly suppressed (Fig.…”

Section: Discussionmentioning

confidence: 99%

Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels

Huang

Miyazawa

Tsuji

2014

Cellular Signalling

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Cobalt chloride has been used as a hypoxia mimetic because it stabilizes hypoxia inducible factor-1α (HIF1-α) and activates gene transcription through a hypoxia responsive element (HRE). However, differences between hypoxia and hypoxia mimetic cobalt chloride in gene regulation remain elusive. Expression of ferritin, the major iron storage protein, is regulated at the transcriptional and posttranscriptional levels through DNA and RNA regulatory elements. Here we demonstrate that hypoxia and cobalt chloride regulate ferritin heavy chain (ferritin H) expression by two distinct mechanisms. Both hypoxia and cobalt chloride increased HIF1-α but a putative HRE in the human ferritin H gene was not activated. Instead, cobalt chloride but not hypoxia activated ferritin H transcription through an antioxidant responsive element (ARE), to which Nrf2 was recruited. Intriguingly, cobalt chloride downregulated ferritin H protein expression while upregulated other ARE-regulated antioxidant genes in K562 cells. Further characterization demonstrated that cobalt chloride increased interaction between iron regulatory proteins (IRP1 and IRP2) and iron responsive element (IRE) in the 5′UTR of ferritin H mRNA, resulting in translational block of the accumulated ferritin H mRNA. In contrast, hypoxia had marginal effect on ferritin H transcription but increased its translation through decreased IRP1-IRE interaction. These results suggest that hypoxia and hypoxia mimetic cobalt chloride employ distinct regulatory mechanisms through the interplay between DNA and mRNA elements at the transcriptional and post-transcriptional levels.

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Section: Discussionmentioning

confidence: 99%

Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels

Huang

Miyazawa

Tsuji

2014

Cellular Signalling

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“…As both mitochondria and TfR-mediated iron loading are simultaneously required for haeme synthesis, and the removal of both mitochondria and TfR are tightly regulated in erythroid cell maturation, these mechanisms are likely to be synchronized. A previous report found that ROS promoted translation of TfR thereby prolonging iron loading 45 . We propose that the continued presence of mitochondria in maturing erythroid cells is signalled to TfR through subtle ROS signalling, and is magnified by mtDNA mutagenesis.…”

Section: Discussionmentioning

confidence: 99%

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

et al. 2015

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Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

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“…Because they merely misregulated ferritin and TfR1 expression in the kidney and the brown fat, tissues with the highest abundance of IRP1, it was proposed that Irp2 dominates cellular iron metabolism in tissues, with Irp1 having an auxiliary physiological function (Meyron-Holtz et al, 2004a). In addition, Irp1 −/− (and Irp2 −/− ) mice did not exhibit any defects when challenged with turpentine to induce an inflammatory response (Viatte et al, 2009), despite the fact that IRPs are modulated in cultured cells by inflammatory reactive species such as H 2 O 2 and NO (Weiss et al, 1993; Pantopoulos and Hentze, 1995; Wang et al, 2005; Hausmann et al, 2011). …”

Section: Mouse Models With Ubiquitous Aberration In the Ire/irp Systemmentioning

confidence: 99%

The IRP/IRE system in vivo: insights from mouse models

Wilkinson¹,

Pantopoulos²

2014

Front. Pharmacol.

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276

239

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Iron regulatory proteins 1 and 2 (IRP1 and IRP2) post-transcriptionally control the expression of several mRNAs encoding proteins of iron, oxygen and energy metabolism. The mechanism involves their binding to iron responsive elements (IREs) in the untranslated regions of target mRNAs, thereby controlling mRNA translation or stability. Whereas IRP2 functions solely as an RNA-binding protein, IRP1 operates as either an RNA-binding protein or a cytosolic aconitase. Early experiments in cultured cells established a crucial role of IRPs in regulation of cellular iron metabolism. More recently, studies in mouse models with global or localized Irp1 and/or Irp2 deficiencies uncovered new physiological functions of IRPs in the context of systemic iron homeostasis. Thus, IRP1 emerged as a key regulator of erythropoiesis and iron absorption by controlling hypoxia inducible factor 2α (HIF2α) mRNA translation, while IRP2 appears to dominate the control of iron uptake and heme biosynthesis in erythroid progenitor cells by regulating the expression of transferrin receptor 1 (TfR1) and 5-aminolevulinic acid synthase 2 (ALAS2) mRNAs, respectively. Targeted disruption of either Irp1 or Irp2 in mice is associated with distinct phenotypic abnormalities. Thus, Irp1−/− mice develop polycythemia and pulmonary hypertension, while Irp2−/− mice present with microcytic anemia, iron overload in the intestine and the liver, and neurologic defects. Combined disruption of both Irp1 and Irp2 is incombatible with life and leads to early embryonic lethality. Mice with intestinal- or liver-specific disruption of both Irps are viable at birth but die later on due to malabsorption or liver failure, respectively. Adult mice lacking both Irps in the intestine exhibit a profound defect in dietary iron absorption due to a “mucosal block” that is caused by the de-repression of ferritin mRNA translation. Herein, we discuss the physiological function of the IRE/IRP regulatory system.

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Redox control of iron regulatory protein 2 stability

Cited by 28 publications

References 37 publications

Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels

Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

The IRP/IRE system in vivo: insights from mouse models

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