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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-03-0773.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 348-350
RED CELLS
Brief report
Hypoxic up-regulation of erythroid 5-aminolevulinate
synthase
Thomas Hofer,
Roland H. Wenger,
Marianne F. Kramer,
Gloria C. Ferreira, and
Max Gassmann
From the Institute of Veterinary Physiology, University
of Zurich, Switzerland; Carl-Ludwig-Institute of
Physiology, University of Leipzig, Germany; and Department
of Biochemistry and Molecular Biology, College of Medicine, University
of South Florida, Tampa.
The erythroid-specific isoform of 5-aminolevulinate synthase
(ALAS2) catalyzes the rate-limiting step in heme biosynthesis. The
hypoxia-inducible factor-1 (HIF-1) transcriptionally up-regulates erythropoietin, transferrin, and transferrin receptor, leading to
increased erythropoiesis and hematopoietic iron supply. To test the
hypothesis that ALAS2 expression might be regulated by a similar
mechanism, we exposed murine erythroleukemia cells to hypoxia (1%
O2) and found an up to 3-fold up-regulation of ALAS2 mRNA
levels and an increase in cellular heme content. A fragment of the
ALAS2 promoter ranging from  716 to +1 conveyed hypoxia responsiveness
to a heterologous luciferase reporter gene construct in transiently
transfected HeLa cells. In contrast, iron depletion, known to induce
HIF-1 activity but inhibit ALAS2 translation, did not increase ALAS2
promoter activity. Mutation of a previously predicted HIF-1-binding
site (323/318) within this promoter fragment and DNA-binding assays
revealed that hypoxic up-regulation is independent of this putative
HIF-1 DNA-binding site.
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