Abstract
Aberrant expression of vascular endothelial growth factor (VEGF) has been demonstrated to be associated with most human solid tumors. Here we report that TGF-beta potently induces VEGF expression in human HT-1080 fibrosarcomas primarily through transcriptional activation with no significant changes in mRNA turnover. The tyrosine kinase inhibitor genistein and AP-1 inhibitor curcumin significantly blocked TGF-beta induction of VEGF expression while SP-1 and MKK1 inhibitors did not. TGF-beta enhanced both AP-1 and HIF-1 DNA binding activities whereas SP-1, AP-2 and NF-1 did not show major changes. Transcriptional reporter assays provided further evidence that TGF-beta augmented both AP-1 and HIF-1 activities. Moreover, TGF-beta-treated HT-1080 cells contained higher levels of HIF-1alpha and c-jun proteins in nuclear extracts. TGF-beta and hypoxia synergistically induced VEGF mRNA expression. Given the fact that most tumors respond to hypoxic stress with increased VEGF expression via HIF-1-dependent transcription, this study identifies for the first time that TGF-beta also increases VEGF mRNA in an AP-l/HIF-1-dependent mechanism and may potentiate the hypoxic response.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Blotting, Western
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Cell Hypoxia
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DNA-Binding Proteins / metabolism*
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Endothelial Growth Factors / biosynthesis*
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Endothelial Growth Factors / genetics
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Enzyme Inhibitors / pharmacology
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Genes, Reporter
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines / biosynthesis*
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Lymphokines / genetics
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Nuclear Proteins / metabolism*
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Proto-Oncogene Proteins c-jun / analysis
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RNA, Messenger / metabolism
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Trans-Activators / metabolism*
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Transcription Factor AP-1 / metabolism*
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Transcription Factors / analysis
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Transcription Factors / metabolism
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Transcriptional Activation
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Transforming Growth Factor beta / pharmacology*
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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DNA-Binding Proteins
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Endothelial Growth Factors
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Enzyme Inhibitors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines
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Nuclear Proteins
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Trans-Activators
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Transcription Factor AP-1
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Transcription Factors
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Transforming Growth Factor beta
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors