Hepatocyte nuclear factor 4α Isoforms originated from the P1 promoter are expressed in human pancreatic β-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms
Hepatocyte nuclear factor 4α Isoforms originated from the P1 promoter are expressed in human pancreatic β-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms
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DOI：
10.1210/en.2002-0024
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发表时间：
2003-05-01
期刊：
影响因子：
4.8
通讯作者：
Laine, B
中科院分区：
文献类型：
--
作者：
Eeckhoute, J;Moerman, E;Laine, B
核受体肝细胞核因子（HNF）4 α参与转录网络，并在胰腺β细胞中发挥重要作用。HNF 4 α基因突变与年轻人的成熟型糖尿病相关HNF 4 α亚型由启动子P1和P2的选择性剪接和选择性使用引起。最近有报道称，HNF 4 α的转录几乎完全由胰岛中的P2启动子驱动。我们观察到来自P1和P2启动子的转录物在人胰腺β细胞和胰腺β细胞系RIN m5 F和HIT-T15中表达。通过免疫检测证实源自P1启动子的HNF 4 α蛋白的表达。由于激活功能模块AF-1的存在，源自P1启动子的HNF 4 α亚型表现出比P2启动子驱动的亚型更强的转录活性和更有效地募集共激活因子。相反，由两个启动子产生的异构体的活动同样受到辅阻遏物小异源二聚体伴侣的抑制。这些行为在β细胞功能所需的HNF 1 α启动子上观察到。我们的研究结果强调了P1启动子驱动的亚型的表达在胰腺β细胞功能的控制中是重要的。
The nuclear receptor hepatocyte nuclear factor (HNF) 4alpha is involved in a transcriptional network and plays an important role in pancreatic beta-cells. Mutations in the HNF4alpha gene are correlated with maturity-onset diabetes of the young 1. HNF4alpha isoforms result from both alternative splicing and alternate usage of promoters P1 and P2. It has recently been reported that HNF4alpha transcription is driven almost exclusively by the P2 promoter in pancreatic islets. We observed that transcripts from both P1 and P2 promoters were expressed in human pancreatic beta-cells and in the pancreatic beta-cell lines RIN m5F and HIT-T15. Expression of HNF4alpha proteins originating from the P1 promoter was confirmed by immunodetection. Due to the presence of the activation function module AF-1, HNF4alpha isoforms originating from the P1 promoter exhibit stronger transcriptional activities and recruit coactivators more efficiently than isoforms driven by the P2 promoter. Conversely, activities of isoforms produced by both promoters were similarly repressed by the corepressor small heterodimer partner. These behaviors were observed on the promoter of HNF1alpha that is required for beta-cell function. Our results highlight that expression of P1 promoter-driven isoforms is important in the control of pancreatic beta-cell function.