The gamma-glutamylcysteine synthetase and glutathione regulate asbestos-induced expression of activator protein-1 family members and activity.
The gamma-glutamylcysteine synthetase and glutathione regulate asbestos-induced expression of activator protein-1 family members and activity.
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γ-谷氨酰半胱氨酸合成酶和谷胱甘肽调节石棉诱导的激活蛋白 1 家族成员的表达和活性。
DOI：
10.1158/0008-5472.can-04-1365
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Mossman,BrookeT
中科院分区：
文献类型：
--
作者：
Shukla,Arti;Flanders,Trisha;Lounsbury,KarenM;Mossman,BrookeT
天冬氨酸纤维导致肺上皮细胞和间皮细胞中激活蛋白-1（AP-1）家族成员原癌基因的持续增加，这些原癌基因与增殖和细胞转化有关。利用肺上皮细胞，肺癌的祖细胞，我们报告，青石棉首先耗尽细胞内的谷胱甘肽，随后上调γ-谷氨酰半胱氨酸合成酶的催化和修饰亚基。在体内石棉吸入实验证实增加γ-谷氨酰半胱氨酸合成酶在小鼠肺中的蛋白水平。我们还发现石棉诱导的原癌基因fos/jun的mRNA水平、fra-1的反式激活和AP-1与DNA的结合活性是谷胱甘肽依赖的。N-乙酰-L-半胱氨酸阻断了石棉对表皮生长因子受体的激活作用，提示这是一个初始的氧化还原激活事件，导致下游AP-1原癌基因上调。γ-谷氨酰半胱氨酸合成酶亚基的过表达完全阻断石棉诱导的AP-1原癌基因表达的上调。然而，当单独过表达时，修饰亚基比催化亚基具有更显著的效果。我们的工作表明，谷胱甘肽控制的上皮细胞的氧化还原状态在石棉诱导的表皮生长因子受体和原癌基因激活以及AP-1活性中起着至关重要的作用。
Asbestos fibers cause persistent increases in activator protein-1 (AP-1) family member proto-oncogenes in lung epithelial and mesothelial cells that are linked to proliferation and cell transformation. Using lung epithelial cells, the progenitor cells of lung cancers, we report that crocidolite asbestos initially depletes intracellular glutathione followed by up-regulation of both catalytic and modifier subunits of γ-glutamylcysteine synthetase.In vivoasbestos inhalation experiments confirm increased protein levels of γ-glutamylcysteine synthetase in mouse lungs. We also show that asbestos-induced mRNA levels offos/junproto-oncogenes,fra-1transactivation, and AP-1 to DNA binding activity are glutathione-dependent. Epidermal growth factor receptor activity by asbestos is blocked byN-acetyl-l-cysteine, suggesting that it is an initial redox-activated event leading to downstream AP-1 proto-oncogene up-regulation. The overexpression of subunits of γ-glutamylcysteine synthetase in combination completely blocked asbestos-induced up-regulation of AP-1 proto-oncogene expression. However, when overexpressed individually, the modifier subunit had more dramatic effects than the catalytic subunit. Our work shows that the glutathione-controlled redox status of the epithelial cell plays a pivotal role in asbestos-induced epidermal growth factor receptor and proto-oncogene activation as well as AP-1 activity.