Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity.
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.
Agani
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Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA.
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D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D001483:Base Sequence; D015687:Cell Hypoxia / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D018197:Hepatoblastoma / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008113:Liver Neoplasms / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008634:Mersalyl / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016587:Antimutagenic Agents; D002614:Chelating Agents; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D003035:Cobalt; D008634:Mersalyl; D004247:DNA; D017526:Receptor, IGF Type 1; D010751:Phosphopyruvate Hydratase; C018021:cobaltous chloride; D003676:Deferoxamine