Kwak Mi-Kyoung, Wakabayashi Nobunao, Greenlaw Jennifer L, Yamamoto Masayuki, Kensler Thomas W
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
Mol Cell Biol. 2003 Dec;23(23):8786-94. doi: 10.1128/MCB.23.23.8786-8794.2003.
Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival. Neurodegenerative and other age-related disorders are associated with reduced proteasome activity. We show herein that expression of most subunits of 20S and 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers of mice following treatment with dithiolethiones, which act as indirect antioxidants. Subunit protein levels and proteasome activity were coordinately increased. No induction was seen in mice where the transcription factor Nrf2 was disrupted. Promoter activity of the PSMB5 subunit of the 20S proteasome increased with either Nrf2 overexpression or treatment with antioxidants in mouse embryonic fibroblasts. Tandem antioxidant response elements in the proximal promoter of PSMB5 that controlled these responses were identified. We propose that induction of the 26S proteasome through the Nrf2 pathway represents an important indirect action of these antioxidants that can contribute to their protective effects against chronic diseases.
蛋白酶体可降解氧化应激过程中形成的受损蛋白质，从而促进细胞存活。神经退行性疾病和其他与年龄相关的疾病与蛋白酶体活性降低有关。我们在此表明，在用作为间接抗氧化剂的二硫代硫酮处理后的小鼠肝脏中，共同组装26S蛋白酶体的20S和19S蛋白酶体的大多数亚基的表达增强了三倍。亚基蛋白水平和蛋白酶体活性协同增加。在转录因子Nrf2被破坏的小鼠中未观察到诱导现象。在小鼠胚胎成纤维细胞中，20S蛋白酶体的PSMB5亚基的启动子活性随着Nrf2过表达或抗氧化剂处理而增加。确定了控制这些反应的PSMB5近端启动子中的串联抗氧化反应元件。我们提出，通过Nrf2途径诱导26S蛋白酶体代表了这些抗氧化剂的一种重要间接作用，这可能有助于它们对慢性疾病的保护作用。
