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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

Mersalyl Is a Novel Inducer of Vascular Endothelial Growth Factor Gene Expression and Hypoxia-Inducible Factor 1 Activity

Faton Agani and Gregg L. Semenza
Molecular Pharmacology November 1998, 54 (5) 749-754; DOI: https://doi.org/10.1124/mol.54.5.749
Faton Agani
Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914
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Gregg L. Semenza
Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914
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Abstract

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 O2availability. 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 andVEGF 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.

Footnotes

    • Received July 14, 1998.
    • Accepted August 7, 1998.
  • Send reprint requests to: Gregg L. Semenza, M.D., Ph.D. The Johns Hopkins Hospital, CMSC-1004, 600 N. Wolfe St., Baltimore, MD 21287-3914. E-mail: gsemenza{at}jhmi.edu

  • G.L.S. is an Established Investigator of the American Heart Association. This work was supported in part by grants from the American Heart Association National Center and the National Institutes of Health (R01-DK39869 and R01-HL55338).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Rapid CommunicationAccelerated Communication

Mersalyl Is a Novel Inducer of Vascular Endothelial Growth Factor Gene Expression and Hypoxia-Inducible Factor 1 Activity

Faton Agani and Gregg L. Semenza
Molecular Pharmacology November 1, 1998, 54 (5) 749-754; DOI: https://doi.org/10.1124/mol.54.5.749

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Rapid CommunicationAccelerated Communication

Mersalyl Is a Novel Inducer of Vascular Endothelial Growth Factor Gene Expression and Hypoxia-Inducible Factor 1 Activity

Faton Agani and Gregg L. Semenza
Molecular Pharmacology November 1, 1998, 54 (5) 749-754; DOI: https://doi.org/10.1124/mol.54.5.749
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