HIF-1α, 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

Michael J. Gray, Jing Zhang, Lee M. Ellis, Gregg L. Semenza, Douglas B. Evans, Stephanie S. Watowich, Gary E. Gallick

Research output: Contribution to journalArticlepeer-review

Abstract

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-1α and increased phosphorylation of signal and transducer of transcription 3 (STAT3). STAT3 and hypoxia-inducible factor (HIF)-1α 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-1α-containing promoter complexes. Inhibition of DNA binding by expression of either STAT3 or HIF-1α dominant negative mutants significantly reduces VEGF expression. These data suggest that the binding of both STAT3 and HIF-1α to the VEGF promoter is required for maximum transcription of VEGF mRNA following hypoxia.

Original languageEnglish (US)
Pages (from-to)3110-3120
Number of pages11
JournalOncogene
Volume24
Issue number19
DOIs
StatePublished - Apr 28 2005

Keywords

  • Angiogenesis
  • HIF-1α VEGF
  • Hypoxia
  • STAT3
  • Src

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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