Role of AP-1 and HIF-1 transcription factors in TGF-beta activation of VEGF expression.
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.
Shih
S C
SC
Department of Opthalmology, Children's Hospital, Boston, MA 02139, USA.
Claffey
K P
KP
D015153:Blotting, Western; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors