Qiao N, Xu C, Zhu Y-X, Cao Y, Liu D-C, Han X
Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
Cell Death Dis. 2015 Feb 19;6(2):e1650. doi: 10.1038/cddis.2015.8.
Hypoxia complicates islet isolation for transplantation and may contribute to pancreatic β-cell failure in type 2 diabetes. Pancreatic β-cells are susceptible to hypoxia-induced apoptosis. Severe hypoxic conditions during the immediate post-transplantation period are a main non-immune factor leading to β-cell death and islet graft failure. In this study, we identified the transcription factor Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells. Hypoxia regulates Ets-1 at multiple levels according to the degree of β-cell oxygen deprivation. Moderate hypoxia promotes Ets-1 gene transcription, whereas severe hypoxia promotes its transactivation activity, as well as its ubiquitin-proteasome mediated degradation. This degradation causes a relative insufficiency of Ets-1 activity, and limits the transactivation effect of Ets-1 on downstream hypoxic-inducible genes and its anti-apoptotic function. Overexpression of ectopic Ets-1 in MIN6 and INS-1 cells protects them from severe hypoxia-induced apoptosis in a mitochondria-dependent manner, confirming that a sufficient amount of Ets-1 activity is critical for protection of pancreatic β-cells against hypoxic injury. Targeting Ets-1 expression may be a useful strategy for islet graft protection during the immediate post-transplantation period.
缺氧会使胰岛移植分离过程复杂化，并可能导致2型糖尿病患者的胰腺β细胞功能衰竭。胰腺β细胞对缺氧诱导的凋亡很敏感。移植后即刻的严重缺氧状况是导致β细胞死亡和胰岛移植失败的主要非免疫因素。在本研究中，我们确定转录因子Ets-1（v-ets成红细胞增多症病毒E26癌基因同源物1）是胰腺β细胞中对抗缺氧诱导凋亡的早期反应基因。缺氧根据β细胞缺氧程度在多个水平上调节Ets-1。中度缺氧促进Ets-1基因转录，而严重缺氧则促进其反式激活活性及其泛素-蛋白酶体介导的降解。这种降解导致Ets-1活性相对不足，并限制了Ets-1对下游缺氧诱导基因的反式激活作用及其抗凋亡功能。在MIN6和INS-1细胞中异位过表达Ets-1可通过线粒体依赖性方式保护它们免受严重缺氧诱导的凋亡，证实足够量的Ets-1活性对于保护胰腺β细胞免受缺氧损伤至关重要。靶向Ets-1表达可能是移植后即刻保护胰岛移植的一种有用策略。
