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Science 8 February 2008:
Vol. 319. no. 5864, pp. 825 - 828
DOI: 10.1126/science.1151133
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Reports

A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis

Siobán B. Keel,1* Raymond T. Doty,1* Zhantao Yang,1 John G. Quigley,1{dagger} Jing Chen,1 Sue Knoblaugh,2 Paul D. Kingsley,3 Ivana De Domenico,4 Michael B. Vaughn,4 Jerry Kaplan,4 James Palis,3 Janis L. Abkowitz1{ddagger}

Hemoproteins are critical for the function and integrity of aerobic cells. However, free heme is toxic. Therefore, cells must balance heme synthesis with its use. We previously demonstrated that the feline leukemia virus, subgroup C, receptor (FLVCR) exports cytoplasmic heme. Here, we show that FLVCR-null mice lack definitive erythropoiesis, have craniofacial and limb deformities resembling those of patients with Diamond-Blackfan anemia, and die in midgestation. Mice with FLVCR that is deleted neonatally develop a severe macrocytic anemia with proerythroblast maturation arrest, which suggests that erythroid precursors export excess heme to ensure survival. We further demonstrate that FLVCR mediates heme export from macrophages that ingest senescent red cells and regulates hepatic iron. Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance.

1 Division of Hematology, University of Washington, Seattle, WA 98195, USA.
2 Animal Health Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3 Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA.
4 Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA.

* These authors contributed equally to this work.

{dagger} Present address: Division of Hematology-Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.

{ddagger} To whom correspondence should be addressed. E-mail: janabk{at}u.washington.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Identification of a Feline Leukemia Virus Variant That Can Use THTR1, FLVCR1, and FLVCR2 for Infection.
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Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis.
A. Iolascon, L. De Falco, and C. Beaumont (2009)
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Iron Homeostasis: Recently Identified Proteins Provide Insight into Novel Control Mechanisms.
A.-S. Zhang and C. A. Enns (2009)
J. Biol. Chem. 284, 711-715
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Molecular mechanisms of normal iron homeostasis.
A.-S. Zhang and C. A. Enns (2009)
Hematology 2009, 207-214
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Diamond-Blackfan anemia: a ribosomal puzzle.
I. Dianzani and F. Loreni (2008)
Haematologica 93, 1601-1604
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Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis.
M. A. Rey, S. P. Duffy, J. K. Brown, J. A. Kennedy, J. E. Dick, Y. Dror, and C. S. Tailor (2008)
Haematologica 93, 1617-1626
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Forging a field: the golden age of iron biology.
N. C. Andrews (2008)
Blood 112, 219-230
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Highlights From The Literature.
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Physiology 23, 128-130
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E-Letters:

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Heme-Controlled Protein Synthesis
Heikki Savolainen
Science Online, 25 Mar 2008 [Full text]

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