Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells
Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells
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DOI：
10.1016/j.bbrc.2005.02.072
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发表时间：
2005-04-15
影响因子：
3.1
通讯作者：
Shimomura, I
中科院分区：
文献类型：
--
作者：
Ihara, A;Yamagata, K;Shimomura, I
肝细胞核因子（HNF）4 α基因突变导致一种年轻人成熟型糖尿病（MODY 1），这是一种单基因2型糖尿病，其特征是胰腺β细胞胰岛素分泌受损。HNF 4 α是在肝脏、肾脏、肠和胰岛中表达的转录因子。已经鉴定了HNF 4 α基因的多种剪接变体，并且HNF 4 α 8的同种型（N-末端剪接变体）在胰腺β细胞中表达。然而，胰腺β细胞中HNF 4 α蛋白的表达水平和HNF 4 α 8的转录活性尚不清楚。在本研究中，我们研究了HNF 4 α在β细胞中的表达，并检查了其功能特性。Western blotting和免疫组织化学分析显示，HNF 4 α蛋白在胰岛和INS-1细胞中的表达远低于肝脏。报告基因测定显示，HNF 4 α 8的反式激活潜力显著弱于HNF 4 α 2的反式激活潜力，HNF 4 α 2是肝脏中的主要同种型，这表明HNF 4 α活性的总水平在胰腺β细胞中非常弱。我们还发现HNF 4 α 8的N端A/B区不具有激活功能，C端F区负调控HNF 4 α 8的转录活性。本文提供的信息将有助于更好地了解MODY 1/HNF 4 α糖尿病。(c)2005年爱思唯尔公司All rights reserved.
Mutations in the hepatocyte nuclear factor (HNF) 4 alpha gene cause a form of maturity-onset diabetes of the young (MODY1), which is a monogenic form of type 2 diabetes characterized by impaired insulin secretion by pancreatic beta-cells. HNF4 alpha is a transcription factor expressed in the liver, kidney, intestine, and pancreatic islet. Multiple splice variants of the HNF4 alpha gene have been identified and an isoform of HNF4 alpha 8, an N-terminal splice variant, is expressed in pancreatic beta-cells. However, expression levels of HNF4 alpha protein in pancreatic beta-cells and the transcriptional activity of HNF4 alpha 8 are not yet understood. In the present study, we investigated the expression of HNF4 alpha in beta-cells and examined its functional properties. Western blotting and immunohistochemical analysis revealed that the expression of HNF4 alpha protein in pancreatic islets and INS-1 cells was much lower than in the liver. A reporter gene assay showed that the transactivation potential of HNF4 alpha 8 was significantly weaker than that of HNF4 alpha 2, which is a major isoform in the liver, suggesting that the total level of HNF4 alpha activity is very weak in pancreatic beta-cells. We also showed that the N-terminal A/B region of HNF4 alpha 8 possessed no activation function and C-terminal F region negatively regulated the transcriptional activity of HNF4 alpha 8. The information presented here would be helpful for the better understanding of MODY1/HNF4 alpha diabetes. (c) 2005 Elsevier Inc. All rights reserved.