DOI: 10.1182/blood-2005-05-1809. Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis

Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis
10.1182/blood-2005-05-1809
Crossref journal-article
American Society of Hematology
Blood (234)
Abstract
Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the “standard” post-transcriptional feedback regulation, balancing expression of ferritin (Fer; iron storage) versus transferrin receptor (TfR1; iron uptake) via specific mRNA binding of iron regulatory proteins (IRPs). Although erythroid differentiation involves high levels of incoming iron, TfR1 mRNA stability must be sustained and Fer mRNA translation must not be activated because iron storage would counteract hemoglobinization. Furthermore, translation of the erythroid-specific form of aminolevulinic acid synthase (ALAS-E) mRNA, catalyzing the first step of heme biosynthesis and regulated similarly as Fer mRNA by IRPs, must be ensured. We addressed these questions using mass cultures of primary murine erythroid progenitors from fetal liver, either undergoing sustained proliferation or highly synchronous differentiation. We indeed observed strong inhibition of Fer mRNA translation and efficient ALAS-E mRNA translation in differentiating erythroblasts. Moreover, in contrast to self-renewing cells, TfR1 stability and IRP mRNA binding were no longer modulated by iron supply. These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system.
Bibliography
Schranzhofer, M., Schifrer, M., Cabrera, J. A., Kopp, S., Chiba, P., Beug, H., & MuÌllner, E. W. (2006). Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood, 107(10), 4159â4167.
Authors 7
Matthias Schranzhofer (first)
Manfred Schifrer (additional)
Javier Antonio Cabrera (additional)
Stephan Kopp (additional)
Peter Chiba (additional)
Hartmut Beug (additional)
Ernst W. Müllner (additional)
References 82 Referenced 69
Dates
Type	When
Created	19 years, 7 months ago (Jan. 19, 2006, 9:04 p.m.)
Deposited	2 years, 4 months ago (May 6, 2023, 3:01 a.m.)
Indexed	2 months ago (July 1, 2025, 9:47 p.m.)
Issued	19 years, 3 months ago (May 15, 2006)
Published	19 years, 3 months ago (May 15, 2006)
Published Print	19 years, 3 months ago (May 15, 2006)
Funders 0
None
BibTeX
@article{Schranzhofer_2006, title={Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis}, volume={107}, ISSN={1528-0020}, url={http://dx.doi.org/10.1182/blood-2005-05-1809}, DOI={10.1182/blood-2005-05-1809}, number={10}, journal={Blood}, publisher={American Society of Hematology}, author={Schranzhofer, Matthias and Schifrer, Manfred and Cabrera, Javier Antonio and Kopp, Stephan and Chiba, Peter and Beug, Hartmut and Müllner, Ernst W.}, year={2006}, month=may, pages={4159–4167} }
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  "abstract": "<jats:p>Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the \u201cstandard\u201d post-transcriptional feedback regulation, balancing expression of ferritin (Fer; iron storage) versus transferrin receptor (TfR1; iron uptake) via specific mRNA binding of iron regulatory proteins (IRPs). Although erythroid differentiation involves high levels of incoming iron, TfR1 mRNA stability must be sustained and Fer mRNA translation must not be activated because iron storage would counteract hemoglobinization. Furthermore, translation of the erythroid-specific form of aminolevulinic acid synthase (ALAS-E) mRNA, catalyzing the first step of heme biosynthesis and regulated similarly as Fer mRNA by IRPs, must be ensured. We addressed these questions using mass cultures of primary murine erythroid progenitors from fetal liver, either undergoing sustained proliferation or highly synchronous differentiation. We indeed observed strong inhibition of Fer mRNA translation and efficient ALAS-E mRNA translation in differentiating erythroblasts. Moreover, in contrast to self-renewing cells, TfR1 stability and IRP mRNA binding were no longer modulated by iron supply. These and additional data stemming from inhibition of heme synthesis with succinylacetone or from iron overload suggest that highly efficient utilization of iron in mitochondrial heme synthesis during normal erythropoiesis alters the regulation of iron metabolism via the IRE/IRP system.</jats:p>",
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