The stress-response molecule NR4A1 resists ROS-induced pancreatic beta-cells apoptosis via WT1

Zong Chen; Qin Dandan; Yu Cong; Gao Peng; Chen Jicui; Lu Sumei; Zhang Yuchao; Liu Yuantao; Yang Yingfeng; Pu Zeqing; Li Xia; Fu Yuchang; Guan Qingbo; Wang Xiangdong

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The stress-response molecule NR4A1 resists ROS-induced pancreatic beta-cells apoptosis via WT1

机译：应激 - 反应分子NR4A1抵抗ROS诱导的胰腺β细胞通过WT1凋亡

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Pancreatic beta-cells often face endoplasmic reticulum stress and/or ROS-associated oxidative stress under adverse conditions. Our previous work has verified that NR4A1 protects pancreatic beta-cells from ER -stress induced apoptosis. However, It remains unknown whether NR4A1 is able to protect pancreatic beta-cells against ROS-associated oxidative stress. In the present study, our data showed that NR4A1 protein expression rapidly increased in MIN6 cells upon H2O2 treatment, and overexpression of NR4A1 in MIN6 cells conferred resistance to cell apoptosis induced by H2O2. These results were further substantiated in isolated islets from mice infected with an adenovirus overexpressing NR4A1. 8-hydroxy-2'-deoxyguanosine (8-OHdG) was used as a biomarker for oxidative stress or a marker for ROS damage. We found that the 8-OHdG level in the islets from NR4A1 knockout mice fed with high-fat diet was much higher than that in the islets from parental control mice; and higher apoptotic rate was observed in the islets from NR4A1 KO mice compared to control mice. Further investigation of underlying mechanisms of NR4A1's protective effects showed that NR4A1 overexpression in MIN6 cells reduced Caspase 3 activation caused by H2O2, and increased expression of WT1 and SOD1. There is a putative NR4A1 binding site (-1118 bp to -1111 bp) in WT1 promoter; our data demonstrated that NR4A1 protein physically associates with the WT1 promoter, and enhanced WT1 promoter transactivation and knockdown of WT1 in MIN6 cells induced apoptosis. These findings suggest that NR4A1 protects pancreatic beta-cells against 11202 mediated apoptosis by up-regulating WT1 expression.

机译：在不利条件下，胰腺β细胞通常面临内质网应激和/或ROS相关的氧化应激。我们之前的工作已经证实NR4A1保护胰腺β细胞免受内质网应激诱导的凋亡。然而，NR4A1是否能够保护胰腺β细胞免受ROS相关氧化应激仍不清楚。在本研究中，我们的数据显示，H2O2处理后，MIN6细胞中NR4A1蛋白表达迅速增加，并且NR4A1在MIN6细胞中的过度表达增强了对H2O2诱导的细胞凋亡的抵抗力。这些结果在感染过表达NR4A1腺病毒的小鼠的分离胰岛中得到进一步证实。8-羟基-2'-脱氧鸟苷（8-OHdG）被用作氧化应激的生物标志物或活性氧损伤的标志物。我们发现，喂食高脂饮食的NR4A1基因敲除小鼠胰岛中的8-OHdG水平远高于亲代对照小鼠胰岛中的8-OHdG水平；与对照组小鼠相比，NR4A1 KO小鼠的胰岛细胞凋亡率更高。对NR4A1保护作用潜在机制的进一步研究表明，NR4A1在MIN6细胞中的过度表达降低了H2O2引起的Caspase 3激活，并增加了WT1和SOD1的表达。WT1启动子中存在一个推定的NR4A1结合位点（-1118 bp至-1111 bp）；我们的数据表明，NR4A1蛋白与WT1启动子存在物理关联，并增强了WT1启动子的反式激活和WT1在MIN6细胞诱导的凋亡中的击倒。这些发现表明，NR4A1通过上调WT1的表达，保护胰腺β细胞免受11202介导的凋亡。

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来源
《Cellular Signalling》 |2017年第1期|共11页
作者
Zong Chen; Qin Dandan; Yu Cong; Gao Peng; Chen Jicui; Lu Sumei; Zhang Yuchao; Liu Yuantao; Yang Yingfeng; Pu Zeqing; Li Xia; Fu Yuchang; Guan Qingbo; Wang Xiangdong;
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作者单位

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Dept Lab Med Shandong Prov Qianfoshan Hosp Jinan 250014 Shandong Peoples R China;

Qingdao Municipal Hosp Dept Endocrinol Qingdao 266071 Shandong Peoples R China;

Qingdao Municipal Hosp Dept Endocrinol Qingdao 266071 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

Univ Alabama Birmingham Dept Nutr Sci Birmingham AL 35294 USA;

Shandong Univ Dept Endocrinol Shandong Prov Hosp Jinan 250021 Shandong Peoples R China;

Shandong Univ Sch Med Dept Cell Biol Jinan 250012 Shandong Peoples R China;

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原文格式 PDF
正文语种 eng
中图分类细胞形态学;
关键词
NR4A1; H2O2; Pancreatic beta-cells; Apoptosis; WT1;

机译：NR4A1;H2O2;胰腺β细胞;细胞凋亡;WT1;

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3. Cell death-inducing DFF45-like effector b (Cideb) is present in pancreatic beta-cells and involved in palmitate induced beta-cell apoptosis [J] . LiH., SongY., ZhangL.J., Diabetes/metabolism research and reviews . 2012,第2期

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The stress-response molecule NR4A1 resists ROS-induced pancreatic beta-cells apoptosis via WT1

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