Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells.
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.
Fukuda
Ryo
R
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Hirota
Kiichi
K
Fan
Fan
F
Jung
Young Do
YD
Ellis
Lee M
LM
Semenza
Gregg L
GL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D014157:Transcription Factors; D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; C482128:MAP2K2 protein, human