An essential role for p300/CBP in the cellular response to hypoxia

Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12969-73. doi: 10.1073/pnas.93.23.12969.


p300 and CBP are homologous transcription adapters targeted by the E1A oncoprotein. They participate in numerous biological processes, including cell cycle arrest, differentiation, and transcription activation. p300 and/or CBP (p300/CBP) also coactivate CREB. How they participate in these processes is not yet known. In a search for specific p300 binding proteins, we have cloned the intact cDNA for HIF-1 alpha. This transcription factor mediates hypoxic induction of genes encoding certain glycolytic enzymes, erythropoietin (Epo), and vascular endothelial growth factor. Hypoxic conditions lead to the formation of a DNA binding complex containing both HIF-1 alpha and p300/CBP. Hypoxia-induced transcription from the Epo promoter was specifically enhanced by ectopic p300 and inhibited by E1A binding to p300/CBP. Hypoxia-induced VEGF and Epo mRNA synthesis were similarly inhibited by E1A. Hence, p300/CBP-HIF complexes participate in the induction of hypoxia-responsive genes, including one (vascular endothelial growth factor) that plays a major role in tumor angiogenesis. Paradoxically, these data, to our knowledge for the first time, suggest that p300/ CBP are active in both transformation suppression and tumor development.

Publication types

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

MeSH terms

  • Adenovirus E1A Proteins / antagonists & inhibitors
  • Adenovirus E1A Proteins / metabolism
  • Carcinoma, Hepatocellular
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / metabolism*
  • Cell Hypoxia
  • Cell Line
  • Cytomegalovirus
  • DNA Probes
  • Endothelial Growth Factors / biosynthesis
  • Enhancer Elements, Genetic
  • Erythropoietin / biosynthesis
  • Genes, Reporter
  • Genetic Vectors
  • Glutathione Transferase
  • Humans
  • Liver Neoplasms
  • Luciferases / biosynthesis
  • Lymphokines / biosynthesis
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / metabolism*
  • Osteosarcoma
  • Protein Binding
  • RNA, Messenger / biosynthesis
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / metabolism
  • Trans-Activators*
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Adenovirus E1A Proteins
  • Carrier Proteins
  • DNA Probes
  • Endothelial Growth Factors
  • Lymphokines
  • Nuclear Proteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • citrate-binding transport protein
  • Erythropoietin
  • Luciferases
  • Glutathione Transferase