Faculty Collaboration Database

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

Date

03/01/2005

Pubmed ID

15735682

DOI

10.1038/sj.onc.1208513

Scopus ID

2-s2.0-18844444774 (requires institutional sign-in at Scopus site)   340 Citations

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-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.

Author List

Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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
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