An essential role for p300/CBP in the cellular response to hypoxia.
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.
Dana-Farber Cancer Institute, Boston, MA, USA.
Z
Z
Arany
L E
LE
Huang
R
R
Eckner
S
S
Bhattacharya
C
C
Jiang
M A
MA
Goldberg
H F
HF
Bunn
D M
DM
Livingston
D017500:Adenovirus E1A Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D003587:Cytomegalovirus; D015342:DNA Probes; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004742:Enhancer Elements, Genetic; D004921:Erythropoietin / Q000096:biosynthesis; D017930:Genes, Reporter; D005822:Genetic Vectors; D005982:Glutathione Transferase; D006801:Humans; D008113:Liver Neoplasms; D008156:Luciferases / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000378:metabolism*; D012516:Osteosarcoma; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017500:Adenovirus E1A Proteins; D002352:Carrier Proteins; D015342:DNA Probes; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C020723:citrate-binding transport protein; D004921:Erythropoietin; D008156:Luciferases; D005982:Glutathione Transferase