Is congenital secondary erythrocytosis/polycythemia caused by activating mutations within the HIF-2α iron-responsive element?

Percy, Melanie J.; Sánchez, Mayka; Świerczek, Sabina; McMullin, Mary Frances; Mojica-Henshaw, Mariluz P.; Muckenthaler, Martina U.; Prchal, Josef T.; Hentze, Matthias W.

doi:10.1182/blood-2007-03-082503

Cited by 5 publications

(3 citation statements)

References 9 publications

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“…IRP1-deficient mice that lack this repressor of HIF-2␣ translation show derepressed HIF-2␣ translation in the kidney, elevated Epo serum levels, and a marked transient polycythemia (4,27). It is remarkable, however, that mutations within the HIF-2␣ IRE have been excluded as a frequent cause of congenital secondary erythrocytosis/polycythemia (58). To further strengthen the link between iron and oxygen homeostasis, IRP1 is mainly active when cellular iron levels are low but oxygen levels are sufficient.…”

Section: Iron-dependent Expression Of Hypoxia-regulated Genesmentioning

confidence: 99%

Adaptation of iron requirement to hypoxic conditions at high altitude

Gassmann

Muckenthaler

2015

Journal of Applied Physiology

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Adequate acclimatization time to enable adjustment to hypoxic conditions is one of the most important aspects for mountaineers ascending to high altitude. Accordingly, most reviews emphasize mechanisms that cope with reduced oxygen supply. However, during sojourns to high altitude adjustment to elevated iron demand is equally critical. Thus in this review we focus on the interaction between oxygen and iron homeostasis. We review the role of iron 1) in the oxygen sensing process and erythropoietin (Epo) synthesis, 2) in gene expression control mediated by the hypoxia-inducible factor-2 (HIF-2), and 3) as an oxygen carrier in hemoglobin, myoglobin, and cytochromes. The blood hormone Epo that is abundantly expressed by the kidney under hypoxic conditions stimulates erythropoiesis in the bone marrow, a process requiring high iron levels. To ensure that sufficient iron is provided, Epo-controlled erythroferrone that is expressed in erythroid precursor cells acts in the liver to reduce expression of the iron hormone hepcidin. Consequently, suppression of hepcidin allows for elevated iron release from storage organs and enhanced absorption of dietary iron by enterocytes. As recently observed in sojourners at high altitude, however, iron uptake may be hampered by reduced appetite and gastrointestinal bleeding. Reduced iron availability, as observed in a hypoxic mountaineer, enhances hypoxia-induced pulmonary hypertension and may contribute to other hypoxia-related diseases. Overall, adequate systemic iron availability is an important prerequisite to adjust to high-altitude hypoxia and may have additional implications for disease-related hypoxic conditions.

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Section: Iron-dependent Expression Of Hypoxia-regulated Genesmentioning

confidence: 99%

Adaptation of iron requirement to hypoxic conditions at high altitude

Gassmann

Muckenthaler

2015

Journal of Applied Physiology

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“…Anderson (Anderson et al, 2011) demonstrated that mice with intestinal disruption of EPAS1 (EPAS1 ΔIE ) showed decreased serum iron levels and expression of iron absorption genes, such as divalent metal transporter 1 (DMT1) and Duodenal cytochrome b (Dcytb), in phenylhydrazine-induced erythropoiesis. In contrast, an iron responsive element (IRE) is found in the 5′untranslated region of the EPAS1 sequence, and the translation of the HIF-2α protein can be repressed by the binding of iron regulatory proteins to the 5′IRE of EPAS1 during iron deficiency (Percy et al, 2007). Additionally, elevated HIF-2α levels during hypoxia suppress hepcidin expression by inducing hepatic EPO production, leading to enhanced intestinal iron uptake and release from internal stores (Liu et al, 2012).…”

Section: Erythropoiesismentioning

confidence: 99%

Updated perspective of EPAS1 and the role in pulmonary hypertension

Wang

Hua²,

Fu³

et al. 2023

Front. Cell Dev. Biol.

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Pulmonary hypertension (PH) is a group of syndromes characterized by irreversible vascular remodeling and persistent elevation of pulmonary vascular resistance and pressure, leading to ultimately right heart failure and even death. Current therapeutic strategies mainly focus on symptoms alleviation by stimulating pulmonary vessel dilation. Unfortunately, the mechanism and interventional management of vascular remodeling are still yet unrevealed. Hypoxia plays a central role in the pathogenesis of PH and numerous studies have shown the relationship between PH and hypoxia-inducible factors family. EPAS1, known as hypoxia-inducible factor-2 alpha (HIF-2α), functions as a transcription factor participating in various cellular pathways. However, the detailed mechanism of EPAS1 has not been fully and systematically described. This article exhibited a comprehensive summary of EPAS1 including the molecular structure, biological function and regulatory network in PH and other relevant cardiovascular diseases, and furthermore, provided theoretical reference for the potential novel target for future PH intervention.

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“…5 Iron regulatory protein (IRP-1) binds to the iron-responsive element in the 59 untranslated region of HIF-2a and represses the translation of HIF-2a protein. 6 Ghosh et al previously reported that deletion of Irp1 in mice results in erythrocytosis, pulmonary hypertension, and cardiac fibrosis attributable to translational derepression of Hif-2a.…”

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confidence: 99%