The role of Keap1-Nrf2 system in oxidative stress response of pancreatic β-cells

Keap1-Nrf2系统在胰腺β细胞氧化应激反应中的作用

• 批准号: 22890014
• 负责人: URUNO Akira
• 金额: $ 2.01万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22890014/
• 关键词: Keap1-Nrf2システム; 糖尿病; 酸化ストレス

Nrf2 (NF-E2-related factor 2)is a basic region-leucine zipper-type transcription factor, which belongs to the Cap' n' collar family. Nrf2 is activated by various stresses including electrophiles, reactive oxygen species (ROS), reactive nitrogen species (RNS), and heavy metals, and coordinately induces anti-oxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1)is an adaptor protein for Cullin3-base ubiquitin E3 ligase and acts as a sensor for stresses, which strictly regulates the Nrf2 activity.We found that both Nrf2 and Keap1 are expressed in isolated islets from mice, and expression of Nrf2-target genes is upregulated by electrophiles, ROS and RNS. In addition, theβ-cell-damaged diabetes model mice crossed with Nrf2 hetero knockout showed elevated blood glucose levels and smaller islet size. Thus, these results support our contention that the Keap1-Nrf2 system plays important roles in the maintenance of pancreatic β-cells. The results further suggest that the Keap1-Nrf2 system may be involved in the pathogenesis of diabetes mellitus in stress conditions.

Nrf 2（NF-E2-related factor 2）是一种碱性亮氨酸拉链型转录因子，属于Cap' n' collar家族。Nrf 2被各种应激激活，包括亲电体、活性氧（ROS）、活性氮（RNS）和重金属，并协同诱导抗氧化酶。Keap 1（Kelch-like ECH-associated protein 1）是Cullin 3-base ubiquitin E3 ligase的接头蛋白，是应激的感受器，严格调控Nrf 2的活性，我们发现Nrf 2和Keap 1在小鼠胰岛中均有表达，且Nrf 2靶基因的表达受亲电体、ROS和RNS的上调。此外，与Nrf 2异源敲除杂交的β细胞损伤的糖尿病模型小鼠显示血糖水平升高和胰岛尺寸较小。因此，这些结果支持我们的论点，即Keap 1-Nrf 2系统在胰腺β细胞的维持中起重要作用。这些结果进一步表明，Keap 1-Nrf 2系统可能参与应激条件下糖尿病的发病机制。

项目成果

ストレスと生体反応. Nrf2-Keap1システムによるストレス応答制御

Nrf2-Keap1 系统对应激反应的控制。

• 发表时间: 2010
• 期刊: Diabetes Frontier
• 作者: 宇留野晃;森口尚;山本雅之
• 通讯作者: 山本雅之

Relationship between Silent Brain Infarction and Primary Aldosteronism

无症状性脑梗塞与原发性醛固酮增多症的关系

• 发表时间: 2011
• 作者: Matsuda K;Uruno A;Kudo M;Satoh F;Ito S;Sugawara A
• 通讯作者: Sugawara A

Upregulation of REG Iα accelerates tumor progression in pancreatic cancer with diabetes

• DOI: 10.1002/ijc.25188
• 发表时间: 2010-10
• 期刊: International Journal of Cancer
• 影响因子: 6.4
• 作者: Lin Zhou;Ruifeng Zhang;Lishun Wang;Shaoming Shen;H. Okamoto;A. Sugawara;L. Xia;Xiaoling Wang;N. Noguchi;T. Yoshikawa;A. Uruno;W. Yao;Yao-zong Yuan

核内受容体および肝細胞増殖因子による血管応答機構の解明膵β細胞におけるKeap1-Nrf2システムの役割

阐明核受体和肝细胞生长因子的血管反应机制 Keap1-Nrf2 系统在胰腺 β 细胞中的作用

• 发表时间: 2011
• 期刊: 日本応用酵素協会誌
• 作者: Uruno A;Noguchi N;Matsuda K;Nata K;Yoshikawa T;Chikamatsu Y;Kagechika H;Harigae H;Ito S;Okamoto H;Sugawara A.;宇留野晃
• 通讯作者: 宇留野晃

Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma

• DOI: 10.1111/j.1349-7006.2012.02216.x
• 发表时间: 2012-04-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Inoue, Daisuke;Suzuki, Takashi;Yamamoto, Masayuki
• 通讯作者: Yamamoto, Masayuki