AN ESSENTIAL ROLE FOR P300 CBP IN THE CELLULAR-RESPONSE TO HYPOXIA/

p300 and CBP are homologous transcription adapters targeted by the EIA oncoprotein. They participate in numerous biological processes, inclu ding 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 bi nding proteins, we have cloned the intact cDNA for HIF-1 alpha, This t ranscription factor mediates hypoxic induction of genes encoding certa in glycolytic enzymes, erythropoietin (Epo), and vascular endothelial growth factor. Hypoxic conditions lead to the formation of a DNA bindi ng complex containing both HIF-1 alpha and p300/CBP, Hypoxia-induced t ranscription from the Epo promoter was specifically enhanced by ectopi c p300 and inhibited by E1A binding to p300/CBP, Hypoxia-induced VEGF and Epo mRNA synthesis were similarly inhibited by E1A. Hence, p300/CB P-HIF complexes participate in the induction of hypoxia-responsive gen es, including one (vascular endothelial growth factor) that plays a ma jor role in tumor angiogenesis. Paradoxically, these data, to our know ledge for the first time, suggest that p300/CBP are active in both tra nsformation suppression and tumor development.