Adenine nucleotide (ADP/ATP) translocase 3 participates in the tumor necrosis factor-induced apoptosis of MCF-7 cells
Adenine nucleotide (ADP/ATP) translocase 3 participates in the tumor necrosis factor-induced apoptosis of MCF-7 cells
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DOI：
10.1091/mbc.e06-12-1161
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Gu, Jun
中科院分区：
文献类型：
--
作者：
Yang, Ziqiang;Cheng, Wei;Gu, Jun
线粒体腺嘌呤核苷酸转位酶（ANT）被认为是线粒体通透性转变孔（mtPTP）的组成部分或调节组分，在细胞凋亡过程中控制线粒体通透性转变。然而，ANT 在细胞凋亡中的作用仍不确定，因为从 ANT 敲除小鼠和野生型小鼠中分离出的肝细胞对 TNF 和 Fas 诱导的细胞凋亡同样敏感。在使用逆转录病毒插入介导的随机诱变筛选肿瘤坏死因子 a (TNF-α) 诱导的 MCF-7 人乳腺癌细胞凋亡所需的基因时，我们发现 ANT3 基因参与了 TNF-α 诱导的 MCF-7 细胞细胞死亡。我们进一步发现，在 MCF-7 细胞中，TNF 和氧化应激诱导的细胞死亡选择性地需要 ANT3，但对于其他几种诱导剂诱导的细胞死亡来说，ANT3 是可有可无的。该数据补充了之前从 ANT 敲除研究中获得的数据，表明 ANT 参与了一些细胞凋亡过程。我们发现，在 ANT3 突变体 (ANT3(mut)) 细胞中观察到的对 TNF-α 诱导的细胞凋亡的抵抗与线粒体膜电位和细胞色素 c 释放的调节缺陷有关。它与细胞内 ATP 水平或生存途径无关，支持之前 ANT 调节 mtPTP 的模型。我们的研究提供了支持 ANT 在细胞凋亡中的作用的遗传证据，并表明 ANT 参与细胞死亡是细胞类型和刺激依赖性的。
Mitochondrial adenine nucleotide translocase (ANT) is believed to be a component or a regulatory component of the mitochondrial permeability transition pore (mtPTP), which controls mitochondrial permeability transition during apoptosis. However, the role of ANT in apoptosis is still uncertain, because hepatocytes isolated from ANT knockout and wild-type mice are equally sensitive to TNF- and Fas-induced apoptosis. In a screen for genes required for tumor necrosis factor a (TNF-alpha)-induced apoptosis in MCF-7 human breast cancer cells using retrovirus insertion-mediated random mutagenesis, we discovered that the ANT3 gene is involved in TNF-alpha-induced cell death in MCF-7 cells. We further found that ANT3 is selectively required for TNF- and oxidative stress-induced cell death in MCF-7 cells, but it is dispensable for cell death induced by several other inducers. This data supplements previous data obtained from ANT knockout studies, indicating that ANT is involved in some apoptotic processes. We found that the resistance to TNF-alpha-induced apoptosis observed in ANT3 mutant (ANT3(mut)) cells is associated with a deficiency in the regulation of the mitochondrial membrane potential and cytochrome c release. It is not related to intracellular ATP levels or survival pathways, supporting a previous model in which ANT regulates mtPTP. Our study provides genetic evidence supporting a role of ANT in apoptosis and suggests that the involvement of ANT in cell death is cell type- and stimulus-dependent.