Role of AP-1 and HIF-1 Transcription Factors in TGF-β Activation of VEGF Expression

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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-β potently induces VEGF expression in human HT-1080 fibrosarcomas primarily through transcrip-tional activation with no significant changes in mRNA turnover. The tyrosine kinase inhibitor genistein and AP-1 inhibitor curcumin significantly blocked TGF-β induction of VEGF expression while SP-1 and MKKl inhibitors did not. TGF-β 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-β augmented both AP-1 and HIF-1 activities. Moreover, TGF-β-treated HT-1080 cells contained higher levels of HIF-1α and c-jun proteins in nuclear extracts. TGF-β 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 fmt time that TGF-β also increases VEGF mRNA in an AP-l/HIF-1-dependent mechanism and may potentiate the hypoxic response.