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Vol. 54, Issue 5, 749-754, November 1998
Institute of Genetic Medicine, Departments of Pediatrics and
Medicine, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21287-3914
In response to hypoxia, mammalian cells express multiple gene
products [including erythropoietin (EPO) and vascular endothelial growth factor (VEGF)] that serve to increase O2 delivery,
as well as glucose transporters and glycolytic enzymes (such as enolase 1) that allow metabolic adaptation to decreased O2
availability. Increased transcription of the genes encoding these
proteins in hypoxic cells is mediated by hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. Expression of
HIF-1 and downstream genes can also be induced by exposure of cells to
divalent metals (such as CoCl2) or iron chelators [such as desferrioxamine (DFO)]. We report here that the organomercurial compound mersalyl induced expression of VEGF and enolase 1 mRNA, as
well as HIF-1 activity, in cultured cells. Expression of reporter genes
containing hypoxia response elements from the EPO and
VEGF genes was also induced by mersalyl treatment. However,
mersalyl inhibited endogenous EPO mRNA expression induced by hypoxia,
CoCl2, or DFO. In cells lacking expression of the
insulin-like growth factor-1 receptor, mersalyl did not induce HIF-1
activity or VEGF mRNA expression, whereas induction by hypoxia,
CoCl2, or DFO was unaffected. The mitogen-activated protein
kinase kinase inhibitor PD098059 markedly reduced induction of HIF-1 by
mersalyl but not by hypoxia. These results indicate that mersalyl
induces expression of HIF-1 and a subset of hypoxia-inducible genes by
a mechanism, involving the insulin-like growth factor-1 receptor and
mitogen-activated protein kinase activity, that is distinct from
mechanisms of induction by hypoxia, CoCl2, or DFO.
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