Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer.
Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer.
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DOI：
10.1038/cddis.2014.6
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发表时间：
2014-02-13
影响因子：
9
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中科院分区：
文献类型：
--
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ABT-737是一种原型BH3模拟药物，在小细胞肺癌（SCLC）细胞中，对ABT-737的敏感性在很大范围内变化。我们之前已经证明Noxa（仅bh3促凋亡的BCL-2家族蛋白）的表达是ABT-737敏感性的关键决定因素。我们在这里表明，Noxa调节MCL-1的定位和稳定性，MCL-1是一种抗凋亡成员，从而调节ABT-737的敏感性。Noxa在BH3结构域、线粒体羧基末端靶向结构域或泛素化赖氨酸区域的突变不仅改变了Noxa本身的定位和稳定性，还影响了MCL-1的线粒体定位和磷酸化/泛素化状态，从而调节了对ABT-737的敏感性。利用这些突变蛋白的研究结果表明，Noxa将MCL-1从细胞质中招募到线粒体。MCL-1的易位启动其磷酸化和随后的泛素化，从而触发蛋白酶体介导的降解。Noxa/MCL-1表达和稳定性的精确调控机制可为调控BH3模拟药物或其他化疗试剂诱导的细胞凋亡提供替代靶点。
The sensitivity to ABT-737, a prototype BH3 mimetic drug, varies in a broad range in small cell lung cancer (SCLC) cells. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is the critical determinant of ABT-737 sensitivity. We show here that Noxa regulates the localization and stability of MCL-1, an anti-apoptotic member, which results in modulating ABT-737 sensitivity. Mutations in Noxa within the BH3 domain, the carboxyl terminus mitochondrial targeting domain, or of ubiquitinated lysines not only change the localization and stability of Noxa itself but also affect the mitochondrial localization and phosphorylation/ubiquitination status of MCL-1 and consequently modulate sensitivity to ABT-737. Results of studies utilizing these mutant proteins indicate that Noxa recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation. The precise regulatory mechanisms of Noxa/MCL-1 expression and stability could provide alternative targets to modulate apoptosis induced by BH3 mimetic drugs or other chemotherapeutic reagents.
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