The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development
The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development
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DOI：
10.1073/pnas.0408744102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Du, CY
中科院分区：
文献类型：
--
作者：
Ren, JY;Shi, MG;Du, CY
BIRC 6基因/BIRC6(Bruce/Apollon)编码哺乳动物中的一种凋亡抑制因子和一种嵌合的E2/E3泛素连接酶。布鲁斯在抗细胞凋亡中的生理作用尚不清楚。在这里，我们表明，Bruce的C末端一半，包括UBC结构域的缺失，导致胎盘和卵黄囊中caspase的激活和细胞凋亡，从而导致胚胎死亡。这种凋亡与抑癌基因P53的上调和核定位以及线粒体凋亡的激活有关，包括Bax、Bak和Pidd的上调，Bax和caspase-2的易位到线粒体，细胞色素c和凋亡诱导因子的释放，以及caspase-9和caspase-3的激活。突变的小鼠胚胎成纤维细胞对多种线粒体死亡刺激敏感，但对肿瘤坏死因子耐药。此外，通过RNA干扰消除p53可以挽救Bruce消融诱导的人类细胞系H460的细胞活力。这种活性保护是通过减少促凋亡因子Bax、Bak和Pidd的表达以及阻止caspase-2、-9和-3的激活而产生的。Caspase和Omi的第二线粒体硬化激活剂的数量没有变化。我们认为，P53是Bruce的下游效应因子，在Bruce功能丧失的情况下，P53激活Pidd/caspase-2和Bax/Bak，导致线粒体凋亡。
Baculoviral inhibitor of apoptosis repeat-containing (Birc)6 gene/ BIRC6 (Bruce/APOLLON) encodes an inhibitor of apoptosis and a chimeric E2/E3 ubiquitin ligase in mammals. The physiological role of Bruce in antiapoptosis is unknown. Here, we show that deletion of the C-terminal half of Bruce, including the UBC domain, causes activation of caspases and apoptosis in the placenta and yolk sac, leading to embryonic lethality. This apoptosis is associated with up-regulation and nuclear localization of the tumor suppressor p53 and activation of mitochondrial apoptosis, which includes upregulation of Bax, Bak, and Pidd, translocation of Bax and caspase-2 onto mitochondria, release of cytochrome c and apoptosis-inducing factor, and activation of caspase-9 and caspase-3. Mutant mouse embryonic fibroblasts are sensitive to multiple mitochondrial death stimuli but resistant to TNF. In addition, eliminating p53 by RNA interference rescues cell viability induced by Bruce ablation in human cell line H460. This viability preservation results from reduced expression of proapoptotic factors Bax, Bak, and Pidd and from prevention of activation of caspase-2, -9, and -3. The amount of second mitochondrial-clerived activator of caspase and Omi does not change. We conclude that p53 is a downstream effector of Bruce, and, in response to loss of Bruce function, p53 activates Pidd/caspase-2 and Bax/Bak, leading to mitochondrial apoptosis.