The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption

Anderson, Sheila A.; Nizzi, Christopher P.; Chang, Yuan I.; Deck, Kathryn M.; Schmidt, Paul; Galy, Bruno; Damnernsawad, Alisa; Broman, Aimee Teo; Kendziorski, Christina; Hentze, Matthias W.; Fleming, Mark D.; Zhang, Jing; Eisenstein, Richard S.

doi:10.1016/j.cmet.2013.01.007

Cited by 182 publications

(176 citation statements)

References 38 publications

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“…1B). Although the two IRPs have considerable overlap in their binding specificities, each also has unique specificities (Henderson et al 1996;Anderson et al 2013). A further possibility for the discrepancy is that mutations to IRE B could be in some manner stimulating the endonuclease activity rather than inhibiting residual IRP interactions.…”

Section: Discussionmentioning

confidence: 99%

Transferrin receptor mRNA interactions contributing to iron homeostasis

Rupani

Connell

2016

RNA

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The transferrin receptor is the primary means of iron importation for most mammalian cells and understanding its regulatory mechanisms is relevant to hematologic, oncologic, and other disorders in which iron homeostasis is perturbed. The 3 ′ UTR of the transferrin receptor mRNA contains an instability element that is protected from degradation during iron depletion through interactions of iron regulatory proteins (IRPs) with five iron-responsive elements (IREs). The structural features required for degradation and the site of IRP binding required for in situ protection remain unclear. An RNA-CLIP strategy is described here that identifies the predominant site of IRP-1 interaction within a nontransformed primary cell line. This approach avoided complications associated with the use of elevated concentrations of protein and/or mRNA and detected interactions within the native environment of the mRNA. A compensatory mutagenesis strategy indicates that the instability element at minimum consists of three non-IRE stem-loops that can function additively, suggesting that they are not forming one highly interdependent structure. Although the IREs are not essential for instability, they enhance instability when IRP interactions are inhibited. These results are supportive of a mechanism for a graded response to the intracellular iron resulting from a progressive loss of IRP protection.

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Section: Discussionmentioning

confidence: 99%

Transferrin receptor mRNA interactions contributing to iron homeostasis

Rupani

Connell

2016

RNA

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“…In fact, Irp1 −/− mice exhibit features of Hif2a overexpression and hyperproduction of Epo, while Irp1 constitutive transgenic mice show defects in erythroid differentiation that can be attributed to decreased Hif2a expression. [113][114][115] These observations indicate that Irp1 acts as an iron and oxygen sensor, linking iron metabolism with erythropoiesis via EPO. In iron deficiency, Irp1 suppresses HIF2a and Epo expression to reduced iron availability, consistently with iron-restricted erythropoiesis.…”

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confidence: 92%

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

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b-thalassemias are monogenic disorders characterized by defective synthesis of the b-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the b-globin gene or its regulatory elements have been associated with b-thalassemias. Due to the complexity of the regulation of the b-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of b-globin and abnormal erythropoiesis, as well as current and novel therapies. ABSTRACTThe complex phenotype of b-thalassemias b-thalassemias are monogenic disorders characterized by reduced or no synthesis of the b-globin chain, one of the major components of adult hemoglobin (HbA). Several hundred mutations in the b-globin gene or regulatory elements have been associated with b-thalassemias.

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“…44 While this manuscript was in preparation, erythropoietic abnormalities of IRP1 2/2 mice were also reported by others. 45,46 Ghosh et al 45 further showed that IRP1 2/2 mice develop pulmonary hypertension, an additional pathology shared by Chuvash polycythemia patients 47 and the respective mouse model. 48 Together, the data reported here and elsewhere 45,46 highlight the crucial role of IRP1 as an upstream regulator of erythropoiesis and systemic iron metabolism.…”

Section: 39mentioning

confidence: 99%

IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation

Wilkinson

Pantopoulos

2013

Blood

123

104

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Key Points• IRP1 controls HIF2a mRNA translation in vivo and thereby acts as an upstream regulator of Epo expression. • IRP1 deficiency leads to age-dependent erythropoietic abnormalities and misregulation of body iron metabolism via the HIF2a/Epo pathway.Hypoxia inducible factor 2a (HIF2a) transcriptionally activates several genes in response to hypoxia. Under normoxic conditions, it undergoes oxygen-dependent degradation by the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) system. The presence of an iron-responsive element (IRE) within the 59 untranslated region of HIF2a mRNA suggests a further iron-and oxygen-dependent mechanism for translational regulation of its expression via iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively). We show here that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2a-dependent abnormalities in erythropoiesis and systemic iron metabolism. Thus, 4-to 6-week-old IRP1 2/2 mice exhibit splenomegaly and extramedullary hematopoiesis, which is corrected in older animals. These erythropoietic abnormalities are caused by translational de-repression of HIF2a mRNA and subsequent accumulation of HIF2a, which induces expression of erythropoietin (Epo). Increased levels of circulating Epo lead to reticulocytosis, polycythemia, and suppression of hepatic hepcidin mRNA. This in turn promotes hyperferremia and iron depletion in splenic macrophages due to unrestricted expression of ferroportin. Our data demonstrate that IRP1 is the principal regulator of HIF2a mRNA translation in vivo and provide evidence that translational control of HIF2a expression dominates over PHD/VHL-mediated regulation of HIF2a stability in juvenile IRP1 2/2 mice. (Blood. 2013;122(9):1658-1668

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The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption

Cited by 182 publications

References 38 publications

Transferrin receptor mRNA interactions contributing to iron homeostasis

Transferrin receptor mRNA interactions contributing to iron homeostasis

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation

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