Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation
Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation
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DOI：
10.1042/bj20111648
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发表时间：
2012-04-01
影响因子：
4.1
通讯作者：
Thornalley, Paul J.
中科院分区：
文献类型：
--
作者：
Xue, Mingzhan;Rabbani, Naila;Thornalley, Paul J.
二羰基代谢物MG（甲基乙二醛）的异常细胞蓄积发生在暴露于高葡萄糖浓度、炎症、细胞老化和衰老时。它与蛋白质和DNA的MG加合物含量增加有关，与DNA链断裂和突变增加、线粒体功能障碍和ROS（活性氧簇）形成以及细胞从细胞外基质中脱离有关。MG介导的损伤被Glo 1（谷胱甘肽酶I）的谷胱甘肽依赖性代谢抵消。然而，Glo 1是否对高MG浓度或二羰基应激的反周期具有应激响应性上调尚不清楚。我们在哺乳动物Glo 1基因外显子I的5 '-非翻译区鉴定了一个功能性ARE（抗氧化反应元件）。转录因子Nrf 2（核因子-红细胞2 p45亚基相关因子2）与该ARE结合，增加Glo 1的基础和诱导表达。Nrf 2的激活剂诱导增加。Glo 1 mRNA、蛋白和活性。Glo 1的表达增加降低了MG、MG衍生的蛋白加合物、诱变和细胞脱离的细胞和细胞外浓度。Nrf（-/-）小鼠肝、脑、心、肾和肺Glo 1 mRNA和蛋白表达降低，尿中MG蛋白和核苷酸加合物排泄增加约2倍。我们的结论是，二羰基应激是通过上调Glo 1的Nrf 2应激反应系统，保护蛋白质和DNA的损伤增加和保护细胞功能。
Abnormal cellular accumulation of the dicarbonyl metabolite MG (methylglyoxal) occurs on exposure to high glucose concentrations, inflammation, cell aging and senescence. It is associated with increased MG-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and ROS (reactive oxygen species) formation and cell detachment from the extracellular matrix. MG-mediated damage is countered by glutathione-dependent metabolism by Glo1 (glyoxalase I). It is not known, however, whether Glo1 has stress-responsive up-regulation to counter periods of high MG concentration or dicarbonyl stress. We identified a functional ARE (antioxidant-response element) in the 5'-untranslated region of exon I of the mammalian Glo1 gene. Transcription factor Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) binds to this ARE, increasing basal and inducible expression of Glo1. Activators of Nrf2 induced increased. Glo1 mRNA, protein and activity. Increased expression of Glo1 decreased cellular and extracellular concentrations of MG, MG-derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung Glo1 mRNA and protein were decreased in Nrf(-/-) mice, and urinary excretion of MG protein and nucleotide adducts were increased approximately 2-fold. We conclude that dicarbonyl stress is countered by up-regulation of Glo1 in the Nrf2 stress-responsive system, protecting protein and DNA from increased damage and preserving cell function.