CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression
CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression
复制标题
DOI：
10.1074/jbc.274.13.9013
复制
发表时间：
1999-03-26
影响因子：
4.8
通讯作者：
Hadzopoulou-Cladaras, M
中科院分区：
文献类型：
--
作者：
Dell, H;Hadzopoulou-Cladaras, M
肝细胞核因子-4(HNF-4)是一种富含肝脏的转录因子，在调节大量涉及葡萄糖、胆固醇和脂肪酸代谢的基因以及决定肝脏表型方面起着至关重要的作用。我们以前已经证明HNF-4在N末端(AF-1)和C末端(AF-2)包含转录激活功能，它们协同作用赋予HNF-4充分的活性。在这里，我们表明，HNF-4招募CREB结合蛋白(CBP)共激活基因的启动子上包含功能的HNF-4位点。HNF-4与CBP的N-末端区域(氨基酸1-771)和CBP的C-末端区域(氨基酸1812-2441)相互作用。HNF-4的两个激活功能AF-1和AF-2分别与CBP的N端、N端和C端相互作用。此外，与其他核激素受体不同的是，HNF-4与CBP之间的相互作用是不依赖于配体的。HNF-4募集CBP可增强后者的转录活性。CBP在缺乏HNF-4的情况下不能激活基因表达，而显性阴性形式的HNF-4阻止CBP的转录激活，这表明仅仅招募CBP是不足以增强基因表达的。这些发现表明，CBP作为HNF-4的转录辅助激活因子，为HNF-4的调控功能提供了新的见解。
Hepatocyte nuclear factor-4 (HNF-4) is a liver-enriched transcription factor that is crucial in the regulation of a large number of genes involved in glucose, cholesterol, and fatty acid metabolism and in determining the hepatic phenotype. We have previously shown that HNF-4 contains transcription activation functions at the N terminus (AF-1) and the C terminus (AF-2) which work synergistically to confer full HNF-4 activity. Here, we show that HNF-4 recruits the CREB-binding protein (CBP) coactivator on promoters of genes that contain functional HNF-4 sites. HNF-4 interacts with the N-terminal region of CBP (amino acids 1-771) and the C-terminal region of CBP (amino acids 1812-2441). The two activating functions of HNF-4, AF-1 and AF-2, interact with the N terminus and the N and C terminus of CBP, respectively. In addition, we show that in contrast to the other nuclear hormone receptors the interaction between HNF-4 and CBP is ligand-independent. Recruitment of CBP by HNF-4 results in an enhancement of the transcriptional activity of the latter. CBP does not activate gene expression in the absence of HNF-4, and dominant negative forms of HNF-4 prevent transcriptional activation by CBP, suggesting that the mere recruitment of CBP by HNF-4 is not sufficient for enhancement of gene expression. These findings demonstrate that CBP acts as a transcriptional coactivator for HNF-4 and provide new insights into the regulatory function of HNF-4.