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Characterization of hypoxia-responsive enhancer in the human erythropoietin
gene shows presence of hypoxia-inducible 120-Kd nuclear DNA-binding protein
in erythropoietin-producing and nonproducing cells
I Beck, R Weinmann and J Caro
Cardeza Foundation for Hematologic Research, Department of Medicine,
Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA
19107-5099.
Erythropoietin (Epo) production in response to hypoxia or cobalt is
primarily mediated by activation of transcription of the Epo gene. Recently
an hypoxia responsive enhancer was identified in the 3' flanking region of
the mouse and human Epo genes. Using functional analysis in Hep 3B cells we
define here the minimal enhancer element as a 29-bp segment starting at the
Apa1 site in the 3' flanking region of the human Epo gene. Mutagenesis
studies of the minimal element identified three different areas that are
necessary for full enhancer activity. Electrophoretic mobility shift assays
show the presence of hypoxia- and/or cobalt-inducible nuclear DNA-binding
proteins that bind to one of the active sites of the enhancer. Induction of
hypoxia- binding activity was abolished by Anisomycin, a potent protein
synthesis inhibitor, suggesting that de novo protein synthesis is necessary
for the activation process. Further characterization of DNA- binding
proteins by use of UV light crosslinking identified a protein of molecular
weight of approximately 120-Kd that was present only in hypoxic extracts.
This protein was found to be present in hypoxic nuclear extracts from both
Epo-producing and non-Epo-producing cells, suggesting that it may be
involved in a more generalized mechanism of cellular response to hypoxia.
Volume 82,
Issue 3,
pp. 704-711,
08/01/1993
Copyright © 1993 by The American Society of Hematology
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