Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47
Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47
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DOI：
10.1074/jbc.m506718200
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发表时间：
2005-10-14
影响因子：
4.8
通讯作者：
Shimano, H
中科院分区：
文献类型：
--
作者：
Amemiya-Kudo, M;Oka, J;Shimano, H
胰岛素基因表达受胰腺β细胞特异性因子PDX-1和BETA 2/E47调节。在这里，我们已经证明，胰岛素启动子是一个新的目标SREBP建立作为脂质合成转录因子。对非β细胞中大鼠胰岛素I基因的启动子分析显示，核SREBP-1c通过三个新的SREBP结合位点（SRE）激活胰岛素启动子，其中两个与E-box重叠，E-box是BETA2/ E47的结合位点。胰岛素启动子的SREBP-1c激活通过共表达BETA 2/ E47而显著增强。SREBP-1c/ BETA2/ E47的这种协同激活不是通过SRE介导的，而是通过BETA2/ E47与SREBP-1c物理相互作用的E盒介导的，这表明SREBP作为共激活剂的新功能。这两个顺式DNA区域E1和E2，以适当的距离将它们分开，对于协同作用是必需的，这意味着在DNA环结构中形成SREBP-1c中心点BETA 2中心点E47复合物，用于有效募集CREB结合蛋白/ p300。然而，在PDX 1的存在下，SREBP-1c与BETA 2/E47的协同作用被取消。当内源性PDX-1表达较低时，SREBP-1c介导的胰岛素启动子活化和表达在β细胞系和分离的胰岛中变得明显。这种隐蔽的SREBP-1c作用可能在具有β细胞脂毒性的糖尿病胰岛素表达中起代偿作用。
Insulin gene expression is regulated by pancreatic beta cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-beta cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/ E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/ E47. This synergistic activation by SREBP-1c/ BETA2/ E47 was not mediated through SREs but through the E-boxes on which BETA2/ E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c center dot BETA2 center dot E47 complex in a DNA looping structure for efficient recruitment of CREB- binding protein/ p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in beta cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with beta cell lipotoxicity.