Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase.
Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase.
复制标题
26S 蛋白酶体的抑制会诱导 GLCLC（γ-谷氨酰半胱氨酸合成酶的催化亚基）的表达。
DOI：
10.1006/bbrc.2000.2419
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发表时间：
2000
影响因子：
3.1
通讯作者：
Freeman,ML
中科院分区：
文献类型：
--
作者：
Sekhar,KR;Soltaninassab,SR;Borrelli,MJ;Xu,ZQ;Meredith,MJ;Domann,FE;Freeman,ML
大多数短寿命和长寿命的细胞蛋白质被26 S蛋白酶体（一种大型多催化蛋白酶）的活性降解。其独特的功能使其成为许多重要生理过程的中心调节活动。Lactacystin是一种非常特异的26 S蛋白酶体抑制剂，是证明蛋白酶体依赖性生化调节途径的极好工具。HepG 2细胞暴露于lactacystin导致GLCLC mRNA水平的显著升高，随后GSH浓度增加。GLCLC是编码γ-谷氨酰半胱氨酸合成酶催化亚基的基因，γ-谷氨酰半胱氨酸合成酶是谷胱甘肽（GSH）合成的限速酶。抑制非蛋白酶体、蛋白酶活性不诱导GLCLC。凝胶迁移率变动分析和异源报告载体的CAT活性表达鉴定了GLCLC抗氧化反应元件ARE 4的Nrf 2介导作为lactacystin诱导GLCLC的机制。这些研究已经确定26 S蛋白酶体活性作为谷胱甘肽合成的中心调节途径。
The majority of short- and long-lived cellular proteins are degraded by the activities of the 26S proteasome, a large multi-catalytic protease. Its unique function places it as a central regulatory activity for many important physiological processes. Lactacystin is a very specific 26S proteasome inhibitor and represents an excellent tool for demonstrating that a pathway exhibits proteasome-dependent biochemical regulation. Exposure of HepG2 cells to lactacystin resulted in robust elevation of GLCLC mRNA levels, followed by an increase in GSH concentrations. GLCLC is the gene that encodes the catalytic subunit for γ-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione (GSH). Inhibition of non-proteasome, protease activities did not induce GLCLC. Gel mobility shift assays and expression of CAT activity from heterologous reporter vectors identified Nrf2 mediation of the GLCLC antioxidant response element, ARE4, as the mechanism by which lactacystin induced GLCLC. These studies have identified 26S proteasome activity as a central regulatory pathway for glutathione synthesis.