HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas

Oncogene. 2005 Apr 28;24(19):3110-20. doi: 10.1038/sj.onc.1208513.


Hypoxia stimulates a number of pathways critical to cancer cell survival, including the activation of vascular endothelial growth factor (VEGF) transcription. In normal fibroblasts, hypoxia-induced activation of the protein tyrosine kinase, Src, is required for VEGF expression. We show here in both pancreatic and prostate carcinoma cell lines cobalt chloride (used to mimic hypoxia) -induced VEGF expression requires Src activation and leads to increased steady-state levels of HIF-1alpha and increased phosphorylation of signal and transducer of transcription 3 (STAT3). STAT3 and hypoxia-inducible factor (HIF)-1alpha bind simultaneously to the VEGF promoter, where they form a molecular complex with the transcription coactivators CBP/p300 and Ref-1/APE. Expression of activated Src from an inducible promoter is sufficient to increase VEGF expression and form these STAT3/HIF-1alpha-containing promoter complexes. Inhibition of DNA binding by expression of either STAT3 or HIF-1alpha dominant negative mutants significantly reduces VEGF expression. These data suggest that the binding of both STAT3 and HIF-1alpha to the VEGF promoter is required for maximum transcription of VEGF mRNA following hypoxia.

Publication types

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

MeSH terms

  • Autoradiography
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cobalt / pharmacology
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / biosynthesis*
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Immunoprecipitation
  • Luciferases / metabolism
  • Male
  • Microscopy, Fluorescence
  • Neoplasm Metastasis
  • Neoplasms / metabolism
  • Neovascularization, Pathologic
  • Nuclear Proteins / biosynthesis*
  • Pancreatic Neoplasms / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / metabolism
  • Protein Binding
  • RNA, Messenger / metabolism
  • STAT3 Transcription Factor
  • Signal Transduction
  • Trans-Activators / biosynthesis*
  • Trans-Activators / metabolism*
  • Transcription Factors / biosynthesis*
  • Transcription, Genetic
  • Vascular Endothelial Growth Factor A / metabolism*
  • src-Family Kinases / metabolism


  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Cobalt
  • Luciferases
  • src-Family Kinases
  • APEX1 protein, human
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • cobaltous chloride