Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1)
Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1)
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DOI：
10.1074/jbc.m702228200
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发表时间：
2007-06-15
影响因子：
4.8
通讯作者：
Elam, Marshall B.
中科院分区：
文献类型：
--
作者：
Deng, Xiong;Yellaturu, Chandrahasa;Elam, Marshall B.
胰岛素对脂质生物合成相关基因的诱导在一定程度上是由固醇调节元件结合蛋白-1c(SREBP-1c)介导的。胰岛素通过转录和转录后机制直接调节SREBP-1c。以前，我们已经证明了大鼠SREBP-1c启动子的胰岛素反应顺式作用单元由几个元件组成，其中包括一个类固醇调节元件，两个肝脏X受体元件，以及一些保守的GC盒。在这里，我们系统地剖析了这些GC盒的作用，并报告了SREBP-1c启动子的五个真正的Sp1结合元件决定了其基础激活和胰岛素诱导的激活。异位表达Sp1可加速大鼠SREBP-1c启动子驱动的荧光素酶的表达，胰岛素进一步增强Sp1的反式激活潜能。针对Sp1的小干扰RNA的引入降低了基础和胰岛素诱导的SREBP-1c启动子的激活。我们还发现Sp1与SREBP-1c和LXRα蛋白都有相互作用，并且胰岛素促进了这些相互作用。染色质免疫沉淀研究表明，胰岛素促进了类固醇受体辅活化子-1对SREBP-1c启动子的募集。这些研究发现了一种新的机制，即胰岛素最大限度地激活大鼠SREBP-1c基因的表达是由Sp1及其与其他转录调节蛋白相互作用能力的增强所介导的。
The induction of genes involved in lipid biosynthesis by insulin is mediated in part by the sterol regulatory element-binding protein-1c ( SREBP-1c). SREBP-1c is directly regulated by insulin by transcriptional and post-transcriptional mechanisms. Previously, we have demonstrated that the insulin-responsive cis-acting unit of the rat SREBP-1c promoter is composed of several elements that include a sterol regulatory element, two liver X receptor elements, and a number of conserved GC boxes. Here we systematically dissected the role of these GC boxes and report that five bona fide Sp1-binding elements of the SREBP-1c promoter determine its basal and insulin-induced activation. Luciferase expression driven by the rat SREBP-1c promoter was accelerated by ectopic expression of Sp1, and insulin further enhanced the transactivation potential of Sp1. Introduction of a small interfering RNA against Sp1 reduced both basal and insulin-induced activation of the SREBP-1c promoter. We also found that Sp1 interacted with both SREBP-1c and LXR alpha proteins and that insulin promoted these interactions. Chromatin immunoprecipitation studies revealed that insulin facilitated the recruitment of the steroid receptor coactivator-1 to the SREBP-1c promoter. These studies identify a novel mechanism by which maximal activation of the rat SREBP-1c gene expression by insulin is mediated by Sp1 and its enhanced ability to interact with other transcriptional regulatory proteins.