Abstract
Stimulation of human colon cancer cells with insulin-like growth factor 1 (IGF-1) induces expression of the VEGF gene, encoding vascular endothelial growth factor. In this article we demonstrate that exposure of HCT116 human colon carcinoma cells to IGF-1 induces the expression of HIF-1 alpha, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. In contrast to hypoxia, which induces HIF-1 alpha expression by inhibiting its ubiquitination and degradation, IGF-1 did not inhibit these processes, indicating an effect on HIF-1 alpha protein synthesis. IGF-1 stimulation of HIF-1 alpha protein and VEGF mRNA expression was inhibited by treating cells with inhibitors of phosphatidylinositol 3-kinase and MAP kinase signaling pathways. These inhibitors also blocked the IGF-1-induced phosphorylation of the translational regulatory proteins 4E-BP1, p70 S6 kinase, and eIF-4E, thus providing a mechanism for the modulation of HIF-1 alpha protein synthesis. Forced expression of a constitutively active form of the MAP kinase kinase, MEK2, was sufficient to induce HIF-1 alpha protein and VEGF mRNA expression. Involvement of the MAP kinase pathway represents a novel mechanism for the induction of HIF-1 alpha protein expression in human cancer cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Carcinoma / metabolism*
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Colonic Neoplasms / metabolism*
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism*
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Enzyme Inhibitors / metabolism
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Eukaryotic Initiation Factor-4E / metabolism
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Gene Expression Regulation
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Humans
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Hypoxia / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit
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Insulin-Like Growth Factor I / metabolism*
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Lymphokines / genetics
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Lymphokines / metabolism*
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MAP Kinase Kinase 2
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MAP Kinase Signaling System / physiology*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins / metabolism
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Protein-Tyrosine Kinases / metabolism
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Repressor Proteins / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Ubiquitin / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Endothelial Growth Factors
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Enzyme Inhibitors
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Eukaryotic Initiation Factor-4E
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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Repressor Proteins
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Transcription Factors
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Ubiquitin
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Insulin-Like Growth Factor I
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MAP2K2 protein, human
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Protein-Tyrosine Kinases
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Ribosomal Protein S6 Kinases, 70-kDa
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MAP Kinase Kinase 2
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Mitogen-Activated Protein Kinase Kinases