Nucleic Acids Research, Vol 24, Issue 23 4768-4774, Copyright © 1996 by Oxford University Press
M Gupta and E Goldwasser
Transcription of the erythropoietin (epo) gene is regulated in response to
tissue hypoxia. In this study we show that constructs containing 117 bp of
the epo promoter sequence cloned upstream of a luciferase reporter, respond
to hypoxia when transfected into the human hepatoma cell line, Hep3B. The
sequence -61 to -45 (EP17) relative to the transcription start of the
murine epo gene imparted an approximately 4- fold induction of reporter
gene expression due to hypoxia. Internal deletion of EP17 resulted in loss
of induction by hypoxia without altering basal expression of the 117 bp epo
promoter reporter construct. Mutagenesis studies showed that the bases at
positions -53, - 59, from -49 to -51 and from -55 to -57 are essential for
hypoxic induction. The EP17 sequence is required for the 3' enhancer
element of the epo gene to be maximally functional. Gel shift and UV
cross-linking experiments showed the presence in Hep3B nuclear extracts, of
two protein factors with approximate molecular weights of 52 kDa and 25 kDa
that bind to EP17. Introduction of specific mutations in the EP17 region
that abolish induction by hypoxia, also eliminated the binding of one or
both of these factors. These experiments demonstrate a role for the
proximal region of the epo promoter in hypoxic induction of the epo gene.
ARTICLES
The role of the near upstream sequence in hypoxia-induced expression of the erythropoietin gene
Department of Biochemistry and Molecular Biology, The University of Chicago, IL 60637, USA.
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