Elevation of NR4A3 expression and its possible role in modulating insulin expression in the pancreatic beta cell.
Elevation of NR4A3 expression and its possible role in modulating insulin expression in the pancreatic beta cell.
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NR4A3 表达的升高及其在调节胰腺 β 细胞胰岛素表达中的可能作用
DOI：
10.1371/journal.pone.0091462
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Gao W;Fu Y;Yu C;Wang S;Zhang Y;Zong C;Xu T;Liu Y;Li X;Wang X
背景 NR4A3/NOR-1 是 NR4A 孤儿核受体亚家族的成员，该亚家族包含感知和响应细胞环境中各种刺激的早期反应基因。 NR4A3 在胰腺 β 细胞胰岛素表达中的作用仍不清楚。方法 在用毒胡萝卜素 (TG)、棕榈酸酯 (PA)、衣霉素 (TM) 和二硫苏糖醇 (DTT)（产生细胞应激甚至细胞凋亡的化学物质）处理的胰腺 β 细胞系 MIN6 中检查 NR4A3 的动态变化。我们利用病毒感染技术诱导 NR4A3 或三个缺失突变体的表达，并确定 MIN6 细胞中胰岛素和胰岛素调节基因的表达。结果 TG 和 PA 这两种内质网 (ER) 应激诱导剂能够诱导 MIN6 细胞中未折叠蛋白反应 (UPR) 激活和 NR4A3 表达升高，而另外两种 ER 应激诱导剂 TM 和 DTT 能够诱导 UPR 激活但不能诱导 NR4A3 升高。腺病毒感染后过表达NR4A3蛋白的MIN6细胞表现出胰岛素基因Ins1和Ins2转录减少，胰岛素蛋白分泌减少，与NR4A3表达水平呈负相关。对NR4A3不同缺失突变体的功能分析表明，删除激活结构域AF1或DNA结合结构域消除了MIN6细胞中NR4A3对胰岛素转录的下调，表明这种下调作用与NR4A3反式激活活性密切相关。 MIN6 细胞中 NR4A3 的过度表达导致胰岛素正调节基因 Pdx1 和 NeuroD1 的 mRNA 转录减少。结论 一些 ER 应激诱导剂，如 TG 或 PA，能够提高 MIN6 细胞中 NR4A3 的表达，而其他诱导剂，如 TM 或 DTT 则不能。 MIN6 细胞中 NR4A3 的过度表达导致胰岛素基因转录和胰岛素分泌下调。 NR4A3 通过调节 Pdx1 和 NeuroD1 的表达来降低胰岛素基因表达。
Background NR4A3/NOR-1 is a member of the NR4A orphan nuclear receptor subfamily, which contains early response genes that sense and respond to a variety of stimuli in the cellular environment. The role of NR4A3 in insulin expression in pancreatic beta cells remains unknown. Methods Dynamic changes in NR4A3 were examined in a pancreatic beta-cell line, MIN6, treated with thapsigargin (TG), palmitate (PA), tunicamycin (TM), and dithiothreitol (DTT), chemicals that produce cell stress and even apoptosis. We exploited virus infection techniques to induce expression of NR4A3 or three deletion mutants, and determined expression of insulin and insulin regulatory genes in MIN6 cells. Results TG and PA, two endoplasmic reticulum (ER) stress inducers, were able to induce unfolded protein response (UPR) activation and elevation of NR4A3 expression in MIN6 cells, whereas TM and DTT, two other ER stress inducers, were able to induce UPR activation but not NR4A3 elevation. MIN6 cells over-expressing NR4A3 protein after adenoviral infection exhibited reduced transcription of the insulin genes Ins1 and Ins2, and reduced insulin protein secretion, which were negatively correlated with NR4A3 expression levels. Functional analysis of different deletion mutants of NR4A3 showed that deleting the activation domain AF1 or the DNA-binding domain abolished the down-regulation of insulin transcription by NR4A3 in MIN6 cells, indicating that this down-regulative role was closely related to the NR4A3 trans-activation activity. Over-expression of NR4A3 in MIN6 cells resulted in reduced mRNA transcription of the insulin positive-regulation genes, Pdx1 and NeuroD1. Conclusion Some ER stress inducers, such as TG or PA, are able to elevate NR4A3 expression in MIN6 cells, while others, such as TM or DTT, are not. Over-expression of NR4A3 in MIN6 cells results in down-regulation of insulin gene transcription and insulin secretion. NR4A3 reduces insulin gene expression by modulating the expression of Pdx1 and NeuroD1.
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影响因子：
12.4
作者：
de Léséleuc, L;Denis, F
通讯作者：
Denis, F
影响因子：
11.4
作者：
Cheng, LEC;Chan, FKM;Winoto, A
通讯作者：
Winoto, A
影响因子：
3.3
作者：
DuRose, Jenny B.;Tam, Arvin B.;Niwa, Maho
通讯作者：
Niwa, Maho
影响因子：
--
作者：
Briand, Olivier;Helleboid-Chapman, Audrey;Lefebvre, Philippe
通讯作者：
Lefebvre, Philippe
DOI：
10.1006/bbrc.1994.2900
发表时间：
1994-12-30
影响因子：
3.1
作者：
OHKURA, N;HIJIKURO, M;MIKI, K
通讯作者：
MIKI, K