Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator
Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator
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DOI：
10.1074/jbc.274.41.28950
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发表时间：
1999-10-08
影响因子：
4.8
通讯作者：
Habener, JF
中科院分区：
文献类型：
--
作者：
Hussain, MA;Habener, JF
在内分泌胰腺中，胰高血糖素基因的α细胞特异性表达由与近端GL启动子元件相互作用的DNA结合蛋白介导，近端GL启动子元件包含几个富含AT的结构域。同源结构域转录因子brain-4、pax-6和cdx-2已被证明与这些位点结合并反式激活胰高血糖素基因表达。在本研究中，我们研究了cdx-2和pax-6与p300的相互作用，p300是一种与基础转录机制偶联的共激活因子。在瞬时转染表达实验中，我们发现cdx-2和pax-6对胰高血糖素基因的反式激活作用被p300的额外表达大大增强。这种增强是由于pax-6和cdx-2与p300的N-末端C/H1结构域的直接蛋白质-蛋白质相互作用。pax-6和cdx-2也在蛋白水平上直接相互作用。pax-6与胰高血糖素G1启动子元件中的DNA识别位点结合，将cdx-2与pax-g和p300的分子复合物连接。此外，我们发现cdx-2的存在增强了pax-g与p300的相互作用，从而建立了与组织特异性胰高血糖素基因表达有关的转录因子与基础转录机制的分子复合物。
In the endocrine pancreas, alpha-cell-specific expression of the glucagon gene is mediated by DNA-binding proteins that interact with the proximal GL promoter element, which contains several AT-rich domains. The homeodomain transcription factors brain-4, pax-6, and cdx-2 have been shown to bind to these sites and to transactivate glucagon gene expression. In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. This enhancement was due to direct protein-protein interactions of both pax-6 and cdx-2 with the N-terminal C/H1 domain of p300. pax-6 and cdx-2 also directly interacted with one another at the protein level. pax-6, bound to its DNA recognition site in the glucagon G1 promoter element, tethered cdx-2 to the molecular complex of pax-g and p300. Further, we found that the presence of cdx-2 enhanced the interaction of pax-g with p300, thus establishing a molecular complex of transcription factors implicated in tissue-specific glucagon gene expression with the basal transcriptional machinery.