Role of AP-1 and HIF-1 transcription factors in TGF-beta activation of VEGF expression

Growth Factors. 2001;19(1):19-34. doi: 10.3109/08977190109001073.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • Cell Hypoxia
  • DNA-Binding Proteins / metabolism*
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Enzyme Inhibitors / pharmacology
  • Genes, Reporter
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins c-jun / analysis
  • RNA, Messenger / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / analysis
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors