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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 491-497
A new transacting factor that modulates hypoxia-induced
expression of the erythropoietin gene
Madhu Gupta,
Paul T. Mungai, and
Eugene Goldwasser
From the Department of Biochemistry and Molecular Biology, The
University of Chicago; and The Heart Institute for Children, Hope
Childrens Hospital, Oak Lawn, IL.
Hypoxia is a strong stimulus for the transcription of a set of
genes, including erythropoietin and vascular endothelial growth factor.
Here we report on the cloning, functional significance, and expression
of a complementary DNA (cDNA) that is involved in hypoxia-mediated
expression of these 2 genes. The full-length cDNA encodes a predicted
protein of 806 amino acids that contains a leucine zipper motif.
This protein, termed HAF for hypoxia-associated factor, binds to
a 17-base pair (bp) region of the erythropoietin promoter, which was
shown earlier to participate in hypoxia-induced expression of the
erythropoietin gene. In Hep3B cells, clones modified to express
HAF antisense RNA showed an attenuated response to
hypoxia-mediated induction of both erythropoietin and vascular endothelial growth factor transcription. HAF showed sequence-specific interaction with a DNA element in the 5' untranslated region of VEGF gene. The HAF 2.6-kilobase (kb) messenger RNA (mRNA) is
expressed in most adult tissues. The highest expression occurs in fetal liver and the least in adult liver. HAF is the murine homolog of
Sart-1, a 125-kd human protein expressed in the nuclei of normal and
malignant cells.
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