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Induction of hypoxia-inducible factor-1, erythropoietin, vascular
endothelial growth factor, and glucose transporter-1 by hypoxia: evidence
against a regulatory role for Src kinase
JM Gleadle and PJ Ratcliffe
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
The induction by hypoxia of genes such as erythropoietin, vascular
endothelial growth factor (VEGF), and glucose transporter-1 (Glut-1) is
mediated in part by a transcriptional complex termed hypoxia-inducible
factor-1 (HIF-1). Several lines of evidence have implicated protein
phosphorylation in the mechanism of activation of HIF-1 by hypoxia. Recent
reports have described the activation of the tyrosine kinase src by severe
hypoxia, and a role in the induction of VEGF by severe hypoxia has been
proposed. This led us to examine whether src and related kinases operated
more widely in the hypoxic induction of HIF-1 and HIF-1-dependent genes
regulated by hypoxia. Measurements of src kinase activity in cells exposed
to varying severities of hypoxia showed activation by severe hypoxia (0.1%
oxygen or catalyst induced anoxia), but not 1% oxygen. This contrasted with
the marked induction of HIF-1 by exposure to 1% oxygen. Manipulations of
src activity were produced by transient and stable transfection of Hep3B
cells. Despite substantial changes in src activity, no alteration was seen
in the normoxic or hypoxic expression of erythropoietin, VEGF, or Glut-1,
or in the regulation of HIF-1-dependent reporter genes inducible by
hypoxia. Similarly, we found that the expression of these genes in src- or
c-src kinase-deficient cells did not differ from wild-type cells at either
1% oxygen or more severe hypoxia. These results indicate that src is not
critical for the hypoxic induction of HIF-1, erythropoietin, VEGF, or
Glut-1.
Volume 89,
Issue 2,
pp. 503-509,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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