The LIM-Homeodomain Protein ISL1 Activates Insulin Gene Promoter Directly through Synergy with BETA2
The LIM-Homeodomain Protein ISL1 Activates Insulin Gene Promoter Directly through Synergy with BETA2
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DOI：
10.1016/j.jmb.2009.07.036
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发表时间：
2009-09-25
影响因子：
5.6
通讯作者：
Zhou, Chun-Yan
中科院分区：
文献类型：
--
作者：
Zhang, Hui;Wang, Wei-Ping;Zhou, Chun-Yan
LIM 同源域转录因子 ISM（胰岛因子 1）对于胰岛细胞和背侧间质发育至关重要。 ISL1 突变与青少年发病的成年糖尿病和 2 型糖尿病有关。 ISL1是否在胰岛素基因表达中发挥作用尚未完全阐明。在本研究中，我们发现ISL1可以与BETA2在胰腺P细胞中协同激活胰岛素基因转录。 ISL1 和 BETA2 的蛋白质-蛋白质相互作用直接由 ISL1 的 LIM 结构域和 BETA2 的基本螺旋-环-螺旋结构域介导。 ISM 的两个 LIM 结构域的缺失增强了胰岛素基因的转录激活，表明同源结构域在激活胰岛素启动子中发挥着关键作用。此外，ISL1可以通过其同源域与大鼠胰岛素基因I启动子中的A3/4盒结合。在 2 型糖尿病（db/db 小鼠模型）中，ISL1 表达在 mRNA 水平上调，但在大鼠胰岛素瘤细胞中被地塞米松下调。这些结果表明ISL1是胰岛素基因表达的转录激活因子，并且ISM与BETA2的相互作用是胰岛素基因转录活性所必需的。 Isl1 基因表达的减少似乎与地塞米松介导的胰岛素表达受损有关。 (C) 2009 Elsevier Ltd. 保留所有权利。
The LIM-homeodomain transcription factor ISM (islet factor 1) is essential for pancreatic islet cell and dorsal mesenchyme development. Mutations in ISL1 are associated with maturity-onset diabetes of the young and type 2 diabetes. Whether ISL1 plays a role in the insulin gene expression has not been fully elucidated. In the present study, we show that ISL1 can synergistically activate insulin gene transcription with BETA2 in pancreatic P cells. The protein-protein interactions of ISL1 and BETA2 are directly mediated by the LIM domains of ISL1 and the basic helix-loop-helix domain of BETA2. Deletion of the two LIM domains of ISM enhances the transcriptional activation of the insulin gene, indicating a key role for the homeodomain in activating the insulin promoter. Furthermore, ISL1 can bind with the A3/4 box in the rat insulin gene I promoter through its homeodomain. ISL1 expression is up-regulated at the mRNA level in type 2 diabetes (db/db mouse model) but down-regulated by dexamethasone in rat insulinoma cells. These results suggest that ISL1 is a transcriptional activator for insulin gene expression, and the interactions of ISM with BETA2 are required for the transcriptional activity of the insulin gene. Reduction in Isl1 gene expression appears to be involved in the impairment of insulin expression mediated by dexamethasone. (C) 2009 Elsevier Ltd. All rights reserved.