Protection of Pancreatic β-Cells from Various Stress Conditions Is Mediated by DJ-1
Protection of Pancreatic β-Cells from Various Stress Conditions Is Mediated by DJ-1
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DOI：
10.1074/jbc.m110.109751
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发表时间：
2010-08-13
影响因子：
4.8
通讯作者：
Linial, Michal
中科院分区：
文献类型：
--
作者：
Inberg, Alex;Linial, Michal
胰腺β细胞易受多种应激，导致功能障碍和凋亡。β细胞功能和质量的恶化与2型糖尿病有关。对维持在不同葡萄糖浓度下的胰腺MIN6细胞进行了比较二维凝胶电泳。在经历高葡萄糖浓度的MIN6细胞中检测到一个蛋白斑点的诱导表达，通过质谱法鉴定为DJ-1的氧化形式。DJ-1 （park7）是一种涉及家族性帕金森病和氧化损伤神经保护的多功能蛋白。在MIN6和β TC-6细胞以及小鼠胰岛暴露于氧化和内质网应激后，DJ-1蛋白及其氧化形式也被诱导。小干扰RNA抑制DJ-1水平可加速细胞死亡，而腺病毒感染增加DJ-1水平可减轻H2O2和thapsigargin诱导的β细胞系和小鼠胰岛细胞死亡。此外，DJ-1以剂量依赖的方式改善了基础应激、氧化应激和内质网应激条件下受调节的胰岛素分泌。我们发现TFII-I （Gtf2i）是胞浆中DJ-1的伙伴，而TFII-I与DJ-1的结合阻止了TFII-I转运到细胞核。结果是应力反应的衰减。我们的研究结果表明，DJ-1与TFII-I协同作用，以应对各种损伤并维持胰腺β细胞功能。
Pancreatic beta-cells are vulnerable to multiple stresses, leading to dysfunction and apoptotic death. Deterioration in beta-cells function and mass is associated with type 2 diabetes. Comparative two-dimensional gel electrophoresis from pancreatic MIN6 cells that were maintained at varying glucose concentrations was carried out. An induced expression of a protein spot, detected in MIN6 cells experiencing high glucose concentration, was identified by mass spectrometry as the oxidized form of DJ-1. DJ-1 (park7) is a multifunctional protein implicated in familial Parkinsonism and neuroprotection in response to oxidative damage. The DJ-1 protein and its oxidized form were also induced following exposure to oxidative and endoplasmic reticulum stress in MIN6 and beta TC-6 cells and also in mouse pancreatic islets. Suppression of DJ-1 levels by small interfering RNA led to an accelerated cell death, whereas an increase in DJ-1 levels by adenovirus-based infection attenuated cell death induced by H2O2 and thapsigargin in beta-cell lines and mouse pancreatic islets. Furthermore, DJ-1 improved regulated insulin secretion under basal as well as oxidative and endoplasmic reticulum stress conditions in a dose-dependent manner. We identified TFII-I (Gtf2i) as DJ-1 partner in the cytosol, whereas the binding of TFII-I to DJ-1 prevented TFII-I translocation to the nucleus. The outcome was attenuation of the stress response. Our results suggest that DJ-1 together with TFII-I operate in concert to cope with various insults and to sustain pancreatic beta-cell function.