Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcumin
Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcumin
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DOI：
10.1016/j.bbamcr.2006.11.004
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发表时间：
2007-03-01
影响因子：
5.1
通讯作者：
Neckers, Len
中科院分区：
文献类型：
--
作者：
Jung, Yunjin;Xu, Wanping;Neckers, Len
我们研究了 ErbB2 蛋白姜黄素消耗的分子机制。姜黄素诱导 ErbB2 泛素化，但用蛋白酶体抑制剂预处理既不能阻止姜黄素消耗 ErbB2 蛋白，也不能进一步积累泛素化的 ErbB2。姜黄素增加内源性和异位表达的 CHIP（一种伴侣依赖性泛素连接酶）与 ErbB2 的关联。在用 ErbB2 和各种 CHIP 质粒共转染并随后进行姜黄素处理的 COS7 细胞中，CHIP-H260Q（一种缺乏泛素连接酶活性的突变体）比野生型 CHIP 更少促进姜黄素诱导的 ErbB2 泛素化，而 CHIP-K30A（一种不能结合 Hsp90 和 Hsp70 的突变体）既不与 ErbB2 相关，也不促进其泛素化。缺乏激酶结构域的 ErbB2 突变体无法与 CHIP 结合，并且完全抵抗姜黄素诱导的泛素化和耗竭。最后，姜黄素的迈克尔反应受体功能是姜黄素与 ErbB2 共价结合以及姜黄素介导的 ErbB2 消耗所必需的。这些数据表明 (1) CHIP 依赖性 ErbB2 泛素化与姜黄素刺激的 ErbB2 耗竭有关，(2) 姜黄素对 ErbB2 的共价修饰是启动该过程的近端信号。 (c) 2006 Elsevier B.V. 保留所有权利。
We investigated the molecular mechanism underlying curcurnin depletion of ErbB2 protein. Curcumin induced ErbB2 ubiquitination but pretreatment with proteasome inhibitors neither prevented curcurnin depletion of ErbB2 protein nor further accumulated ubiquitinated ErbB2. Curcumin increased association of endogenous and ectopically expressed CHIP, a chaperone-dependent ubiquitin ligase, with ErbB2. In COS7 cells cotransfected with ErbB2 and various CHIP plasmids followed by curcurnin treatment, CHIP-H260Q (a mutant lacking ubiquitin ligase activity) promoted less curcumin-induced ErbB2 ubiquitination than did wild type CHIP, and CHIP-K30A (a mutant incapable of binding Hsp90 and Hsp70) neither associated with ErbB2 nor promoted its ubiquitination. ErbB2 mutants lacking the kinase domain failed to associate with CHIP and were completely resistant to ubiquitination and depletion induced by curcumin. Finally, curcumin's Michael reaction acceptor functionality was required for both covalent association of curcurnin with ErbB2 and curcumin-mediated ErbB2 depletion. These data suggest (1) that CHIP-dependent ErbB2 ubiquitination is implicated in curcumin-stimulated ErbB2 depletion, and (2) that covalent modification of ErbB2 by curcurnin is the proximal signal which initiates this process. (c) 2006 Elsevier B.V. All rights reserved.