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首页> 外文会议>NATO Advanced Study Institute on Vascular Endothelium : Mechanisms of Cell Signaling >Regulation of Hepatic Apolipoprotein Gene Transcription by Smad Family Members
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Regulation of Hepatic Apolipoprotein Gene Transcription by Smad Family Members

机译：Smad家族成员调节肝脂蛋白基因转录

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We have reported recently that SMADs, which participate in TGF mediated signal transduction cooperate with the ubiquitous transcription factor Spl to activate hepatic transcription of the p21/WAFl gene. This indicated that SMADs might act as general transactivators of promoters whose transcription depends on Spl and possibly other factors. Here we report that in transient transfections of HepG2 cells, SMADs transactivate the human apolipoprotein C-IH promoter (-890/+24)which contains multiple Spl sites within the distal -790 to -500 region. Among the various SMAD proteins tested, SMADs 3 and 4 showed the greatest transactivation potential (25-fold). A synthetic promoter containing the distal apoC-III (-790/-500) promoter region fused with the minimal AdML promoter was transactivated by SMAD3/4 proteins (4-fold). The proximal apoC-III (-163/+24) promoter region that does not contain Spl binding sites was also transactivated by SMAD3/4 proteins (10-fold). Both the proximal and distal regions contain binding sites for the orphan nuclear receptor HNF-4 that are critical for apoC-IH promoter function. Therefore, we tested putative functional and physical interactions between SMADs and HNF-4. It was found that: a) transactivation of the apoC-III promoter by SMADs was severely reduced in HepG2 cells expressing antisense HNF-4, b) SMADs transactivated Hormone Response Element (HRE)-dependent synthetic promoters synergistically with HNF-4 and c) SMAD3 physically interacted with HNF-4 in vitro protein-protein interaction assays. These findings suggest that i) SMAD proteins can modulate gene transcription by novel mechanisms which involve their physical and functional interaction with hormone nuclear receptors such as HNF-4 and ii) factors which regulate the expression of SMAD proteins in hepatic cells could play an important role in cholesterol homeostasis and lipoprotein metabolism.
机译：我们最近报道了参与TGF介导的信号转导的Smads与普发的转录因子SPL合作以激活P21 / WAFL基因的肝脏转录。这表明SMAD可能充当促进剂的一般反辐期剂，其转录取决于SPL和可能的其他因素。这里，我们报告，在HepG2细胞中的瞬时转染中，Smads的反式激活的人载脂蛋白包含远侧-790〜-500区域内的多个sp1位点C-IH启动子（-890 / + 24）。在测试的各种Smad蛋白中，Smads 3和4显示最大的转移潜力（25倍）。含有与最小ADM1启动子融合的远端Apoc-III（-790 / -500）启动子区域的合成启动子通过Smad3 / 4蛋白（4倍）转灭。近端Apoc-III（-163 / + 24）启动子区，其不含SPL结合位点也通过Smad3 / 4蛋白（10倍）转灭。近端和远端区域均含有对Apoc-1h启动子功能至关重要的孤儿核受体HNF-4的结合位点。因此，我们在Smads和HNF-4之间测试了推定的功能和物理相互作用。发现：a）在表达反义HNF-4，B）的HepG2细胞中，Smads的血栓-III启动子的转基因在表达反义HNF-4，B）中，Smads转移激素响应元件（HRE） - 依赖性合成促进剂与HNF-4和C协同依赖性合成的启动子Smad3与HNF-4体外蛋白质 - 蛋白质相互作用测定物理相互作用。这些发现表明I）Smad蛋白可以通过新的机制调节基因转录，其涉及其与激素核受体如HNF-4和II）的物理和功能相互作用，这些因子调节肝细胞中Smad蛋白的表达可能发挥重要作用在胆固醇稳态和脂蛋白代谢中。

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