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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.

Type

Journal article

Publication Date

1996

Volume

93

Pages

12969 - 12973

Keywords

Adenovirus E1A Proteins/antagonists & inhibitors/metabolism Carcinoma, Hepatocellular Carrier Proteins/biosynthesis/*metabolism Cell Hypoxia Cell Line Cytomegalovirus DNA Probes Endothelial Growth Factors/biosynthesis Enhancer Elements (Genetics) Erythropoietin/biosynthesis Genes, Reporter Genetic Vectors Glutathione Transferase Human Liver Neoplasms Luciferase/biosynthesis Lymphokines/biosynthesis Nuclear Proteins/biosynthesis/*metabolism Osteosarcoma Protein Binding Recombinant Fusion Proteins/biosynthesis/metabolism RNA, Messenger/biosynthesis Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Transcription Factors/biosynthesis/*metabolism Transcription, Genetic Transfection Tumor Cells, Cultured