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.
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.
Mesh Terms:
Anoxia, Autoradiography, Cell Line, Tumor, Chromatin Immunoprecipitation, Cobalt, DNA-(Apurinic or Apyrimidinic Site) Lyase, DNA-Binding Proteins, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Female, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Luciferases, Male, Microscopy, Fluorescence, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Nuclear Proteins, Pancreatic Neoplasms, Phosphorylation, Promoter Regions, Genetic, Prostatic Neoplasms, Protein Binding, RNA, Messenger, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Vascular Endothelial Growth Factor A, src-Family Kinases
Anoxia, Autoradiography, Cell Line, Tumor, Chromatin Immunoprecipitation, Cobalt, DNA-(Apurinic or Apyrimidinic Site) Lyase, DNA-Binding Proteins, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Female, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Luciferases, Male, Microscopy, Fluorescence, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Nuclear Proteins, Pancreatic Neoplasms, Phosphorylation, Promoter Regions, Genetic, Prostatic Neoplasms, Protein Binding, RNA, Messenger, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Vascular Endothelial Growth Factor A, src-Family Kinases
Oncogene
Date: Apr. 28, 2005
PubMed ID: 15735682
View in: Pubmed Google Scholar
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