Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3α-II during cancer cachexia
Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3α-II during cancer cachexia
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DOI：
10.1158/0008-5472.can-04-2102
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发表时间：
2004-11-15
期刊：
影响因子：
11.2
通讯作者：
Han, HQ
中科院分区：
文献类型：
--
作者：
Kwak, KS;Zhou, XL;Han, HQ
骨骼肌的进行性耗竭是许多类型晚期癌症的标志，并且常常与虚弱、发病和死亡相关。肌肉萎缩主要是由泛素蛋白酶体系统的激活介导的，该系统负责降解大量细胞内蛋白质。 E3 泛素连接酶控制多泛素化，这是泛素-蛋白酶体系统中的限速步骤，但它们在癌症中肌肉蛋白分解代谢中的直接参与仍不清楚。在这里，我们报道了 E3alpha-II（一种新型“N 端规则”泛素连接酶）的全长克隆，及其在癌症恶病质中的功能参与。 E3α-II 在骨骼肌中高度富集，其表达受促炎细胞因子调节。在两种不同的癌症恶病质动物模型中，E3α-II 在肌肉萎缩开始和进展过程中被显着诱导。骨骼肌中 E3α-II 的激活伴随着蛋白质泛素化的急剧增加，这可以被精氨酸甲酯（一种 E3α 选择性抑制剂）阻断。用肿瘤坏死因子 a 或白细胞介素 6 处理肌管会引起 E3α-II 表达和泛素结合活性显着增加，但 E3α-I 表达和泛素结合活性不会显着增加。 E3alpha-II 转染显着加速了肌肉培养物中泛素与内源细胞蛋白的缀合。这些发现表明，E3α-II 在癌症恶病质期间的肌肉蛋白分解代谢中发挥重要作用，并表明 E3α-II 是肌肉萎缩的潜在治疗靶点。
The progressive depletion of skeletal muscle is a hallmark of many types of advanced cancer and frequently is associated with debility, morbidity, and mortality. Muscle wasting is primarily mediated by the activation of the ubiquitin-proteasome system, which is responsible for degrading the bulk of intracellular proteins. E3 ubiquitin ligases control polyubiquitination, a rate-limiting step in the ubiquitin-proteasome system, but their direct involvement in muscle protein catabolism in cancer remains obscure. Here, we report the full-length cloning of E3alpha-II, a novel "N-end rule" ubiquitin ligase, and its functional involvement in cancer cachexia. E3alpha-II is highly enriched in skeletal muscle, and its expression is regulated by proinflammatory cytokines. In two different animal models of cancer cachexia, E3alpha-II was significantly induced at the onset and during the progression of muscle wasting. The E3alpha-II activation in skeletal muscle was accompanied by a sharp increase in protein ubiquitination, which could be blocked by arginine methylester, an E3alpha-selective inhibitor. Treatment of myotubes with tumor necrosis factor a or interleukin 6 elicited marked increases in E3alpha-II but not E3alpha-I expression and ubiquitin conjugation activity in parallel. E3alpha-II transfection markedly accelerated ubiquitin conjugation to endogenous cellular proteins in muscle cultures. These findings show that E3alpha-II plays an important role in muscle protein catabolism during cancer cachexia and suggest that E3alpha-II is a potential therapeutic target for muscle wasting.