Pdx-1 enables insulin secretion by regulating synaptotagmin 1 gene expression
Pdx-1 enables insulin secretion by regulating synaptotagmin 1 gene expression
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DOI：
10.1016/j.bbrc.2004.04.071
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发表时间：
2004-06-04
影响因子：
3.1
通讯作者：
Shimizu, A
中科院分区：
文献类型：
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作者：
Nakajima-Nagata, N;Sugai, M;Shimizu, A
Pdx-1在胰腺的发育和维持胰腺β细胞功能中起重要作用。然而. Pdx-1在调节胰岛素释放中的作用尚未完全确定。我们先前证明Pdx-1克服了来自小肝细胞（SHC）的胰岛素产生细胞的胰岛素释放缺陷。在体内，胰岛素分泌是由细胞内Ca 2+浓度增加所触发的一系列事件来调节的，这些事件响应于高葡萄糖浓度。在本研究中，我们确定了一个新的Pdx-1参与胰岛素释放的目标。Pdx-1通过Syt 1基因3'调控区内的Pdx-1结合位点正向调节编码突触结合蛋白1（Syt 1）（在胰岛素释放中起核心作用的Ca 2+传感器）的基因的转录。我们通过基因敲除小丑策略进一步证明了Pdx-1在胰岛素分泌中的重要作用。针对Pdx-1的小干扰RNA（siRNA）特异性降低胰岛素瘤细胞系中Pdx-1蛋白和Syt 1转录物的水平。我们的数据表明，Pdx-1可能有助于通过促进Syt 1在体内的表达调节胰岛素释放，并为未来的糖尿病治疗提供有用的信息。(C)2004爱思唯尔公司All rights reserved.
Pdx-1 plays important roles both in the development of the pancreas and in maintaining pancreatic beta cell function. However. the role of Pdx-1 in the regulation of insulin release is not well established. We previously demonstrated that Pdx-1 overcomes the defect in insulin release from the insulin-producing cells derived from small hepatocytes (SHCs). Insulin secretion is regulated in vivo by the sequential events triggered by the increase of intracellular Ca2+-concentration in response to high glucose concentration. In the present study, we identified a new target of Pdx-1 involved in insulin release. Pdx-1 positively regulates the transcription of the gene encoding synaptotagmin 1 (Syt1) (a Ca2+-sensor that plays a central role in insulin release) through Pdx-1-binding sites within the 3' regulatory region of the Syt1 gene. We further demonstrated the essential role of Pdx-1 in insulin secretion by the gene knock-clown strategy. Small interfering RNA (siRNA) directed against Pdx-1 specifically reduced the levels of Pdx-1 protein and Syt1 transcript in insulinoma lines. Our data indicate that Pdx-1 might contribute to the regulation of insulin release by promoting Syt1 expression in vivo, and provide useful information for future therapy of diabetes mellitus. (C) 2004 Elsevier Inc. All rights reserved.