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Desferrioxamine induces erythropoietin gene expression and hypoxia-
inducible factor 1 DNA-binding activity: implications for models of hypoxia
signal transduction
GL Wang and GL Semenza
Department of Pediatrics, Johns Hopkins University School of Medicine,
Baltimore, MD.
Erythropoietin (EPO) gene transcription is activated in kidney cells in
vivo and in Hep3B cells exposed to hypoxia or cobalt chloride. Hypoxia-
inducible factor 1 (HIF-1) is a nuclear factor that binds to the
hypoxia-inducible enhancer of the EPO gene at a site that is required for
transcriptional activation. HIF-1 DNA-binding activity is induced by
hypoxia or cobalt chloride treatment of Hep3B cells. We report that
treatment of Hep3B cells with desferrioxamine (DFX) induced HIF-1 activity
and EPO RNA expression with kinetics similar to the induction of HIF-1 by
hypoxia or cobalt chloride. Induction by each of these stimuli was
inhibited by cycloheximide, indicating a requirement for de novo protein
synthesis. DFX appears to induce HIF-1 by chelating iron as induction was
inhibited by coadministration of ferrous ammonium sulfate. DFX
administration to mice transiently increased EPO RNA levels in the kidney.
As previously shown for hypoxia and cobalt treatment, DFX also induced
HIF-1 activity in non-EPO-producing cells, suggesting the existence of a
common hypoxia signal-transduction pathway leading to HIF-1 induction in
different cell types.
Volume 82,
Issue 12,
pp. 3610-3615,
12/15/1993
Copyright © 1993 by The American Society of Hematology
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