Degradation of Mcl-1 by β-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization
Degradation of Mcl-1 by β-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization
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DOI：
10.1128/mcb.00620-06
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发表时间：
2007-06-01
影响因子：
5.3
通讯作者：
Hung, Mien-Chie
中科院分区：
文献类型：
--
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
细胞凋亡对胚胎发育、组织动态平衡和肿瘤发生至关重要，并在很大程度上由抗细胞凋亡和存活调节因子的Bcl2家族决定。在这里，我们报道了Mcl-1的降解需要糖原合成酶激酶3(GSK-3)，我们发现了一种新的蛋白酶体介导的Mcl-1转换机制，其中GSK-3β与Mcl-1在一个共同的基序((155)STDG(159)SLps(163)T；磷酸化位点以斜体表示)结合并磷酸化，这将导致Mcl-1与E3连接酶β-TrCP结合，而β-TrCP促进磷酸化的Mcl-1的泛素化和降解。Mcl-1的一种变异体Mcl-1(Mcl-1-3A)可以消除GSK-3β的磷酸化，从而不能被β-TrCP泛素化，它比野生型Mcl-1更稳定，能够阻断GSK-3β的促凋亡功能，并增强化疗耐药性。我们的结果表明，P-TrCP对Mcl-1的转化是GSK-3β诱导细胞凋亡的重要机制，并参与了GSK-3β介导的肿瘤抑制和化疗增敏。
Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3 beta associates with and phosphorylates Mcl-1 at one consensus motif ((155)STDG(159)SLPS(163)T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase beta-TrCP, and beta-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3 beta and then cannot be ubiquitinated by beta-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3 beta and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by P-TrCP is an essential mechanism for GSK-3 beta-induced apoptosis and contributes to GSK-3 beta-mediated tumor suppression and chemosensitization.