An essential role for p300/CBP in the cellular response to hypoxia
An essential role for p300/CBP in the cellular response to hypoxia
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DOI：
10.1073/pnas.93.23.12969
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发表时间：
1996-11-12
影响因子：
11.1
通讯作者：
Livingston, DM
中科院分区：
文献类型：
--
作者：
Arany, Z;Huang, LE;Livingston, DM
p300和CBP是EIA癌蛋白靶向的同源转录衔接子。它们参与许多生物学过程，包括细胞周期停滞、分化和转录激活。p300和/或CBP（p300/CBP）也共同激活CREB，它们如何参与这些过程尚不清楚。在寻找特异性p300结合蛋白的过程中，我们克隆了HIF-1 α的完整cDNA。缺氧条件导致形成含有HIF-1 α和p300/CBP的DNA结合复合物，缺氧诱导的Epo启动子转录被异位p300特异性地增强，并被E1 A与p300/CBP结合所抑制，缺氧诱导的VEGF和Epo mRNA合成被E1 A类似地抑制。因此，p300/CBP-HIF复合物参与低氧应答基因的诱导，包括在肿瘤血管生成中起主要作用的基因（血管内皮生长因子）。有趣的是，据我们所知，这些数据首次表明p300/CBP在转化抑制和肿瘤发展中均具有活性。
p300 and CBP are homologous transcription adapters targeted by the EIA 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.