Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2012 Jun 15;287(25):20866-75. doi: 10.1074/jbc.M112.357293. Epub 2012 Apr 27.
The pro-apoptotic BAX protein contains a BH3 domain that is necessary for its dimerization and for activation of the intrinsic apoptotic pathway. The MUC1 (mucin 1) heterodimeric protein is overexpressed in diverse human carcinomas and blocks apoptosis in the response to stress. In this study, we demonstrate that the oncogenic MUC1-C subunit associates with BAX in human cancer cells. MUC1-C·BAX complexes are detectable in the cytoplasm and mitochondria and are induced by genotoxic and oxidative stress. The association between MUC1-C and BAX is supported by the demonstration that the MUC1-C cytoplasmic domain is sufficient for the interaction with BAX. The results further show that the MUC1-C cytoplasmic domain CQC motif binds directly to the BAX BH3 domain at Cys-62. Consistent with binding to the BAX BH3 domain, MUC1-C blocked BAX dimerization in response to (i) truncated BID in vitro and (ii) treatment of cancer cells with DNA-damaging agents. In concert with these results, MUC1-C attenuated localization of BAX to mitochondria and the release of cytochrome c. These findings indicate that the MUC1-C oncoprotein binds directly to the BAX BH3 domain and thereby blocks BAX function in activating the mitochondrial death pathway.
促凋亡的 BAX 蛋白含有一个 BH3 结构域，该结构域对于其二聚化和固有凋亡途径的激活是必需的。MUC1（黏蛋白 1）异二聚体蛋白在多种人类癌中过表达，并阻止应激反应中的细胞凋亡。在这项研究中，我们证明了致癌的 MUC1-C 亚基与人癌细胞中的 BAX 相关联。MUC1-C·BAX 复合物可在细胞质和线粒体中检测到，并可被遗传毒性和氧化应激诱导。MUC1-C 和 BAX 之间的关联得到了证实，即 MUC1-C 的细胞质结构域足以与 BAX 相互作用。结果进一步表明，MUC1-C 细胞质结构域的 CQC 基序可直接与 BAX BH3 结构域的 Cys-62 结合。与结合 BAX BH3 结构域一致，MUC1-C 阻断了 BAX 在体外（i）截断 BID 和（ii）用 DNA 损伤剂处理癌细胞时的二聚化。与这些结果一致，MUC1-C 减弱了 BAX 向线粒体的定位和细胞色素 c 的释放。这些发现表明，MUC1-C 癌蛋白直接与 BAX BH3 结构域结合，从而阻止 BAX 在激活线粒体死亡途径中的功能。
