DIAP1 suppresses ROS-induced apoptosis caused by impairment of the selD/sps1 homolog in Drosophila
DIAP1 suppresses ROS-induced apoptosis caused by impairment of the selD/sps1 homolog in Drosophila
复制标题
DOI：
10.1242/jcs.00783
复制
发表时间：
2003-11-15
影响因子：
4
通讯作者：
Serras, F
中科院分区：
文献类型：
--
作者：
Morey, M;Corominas, M;Serras, F
细胞抗氧化防御系统可中和称为活性氧 (ROS) 的细胞毒性副产物。其中，硒蛋白具有重要的抗氧化和解毒功能。硒蛋白生物合成的干扰导致活性氧的积累，从而导致有毒的细胞内环境。由此产生的 ROS 失衡会引发细胞凋亡，从而消除有害细胞。在果蝇中，selD 基因（与人类 1 型硒磷酸合成酶同源）的无效突变会导致硒蛋白生物合成受损、ROS 爆发和致死。我们提出这种突变（称为 selD(ptuf)）作为了解 ROS 积累和细胞死亡之间联系的工具。为此，我们分析了果蝇成虫盘中 selD(ptuf) 突变细胞凋亡的机制。 selD(ptuf) 的凋亡作用不需要 Ras/MAPK 依赖性促凋亡基因 hid 的活性，但会导致肿瘤抑制蛋白 Dmp53 的稳定和果蝇促凋亡基因 reaper (rpr) 的转录。我们还提供了遗传证据，表明启动子 caspase DRONC 被激活，效应子 caspase DRICE 被处理以使 selD(ptuf) 突变细胞死亡。此外，凋亡抑制剂 DIAP1 的异位表达可以挽救 selD(ptuf) 突变细胞的细胞活力。这些观察结果表明，果蝇中 selD(ptuf) ROS 诱导的细胞凋亡主要是由 caspase 依赖性 Dmp53/Rpr 途径驱动的。
The cellular antioxidant defense systems neutralize the cytotoxic by-products referred to as reactive oxygen species (ROS). Among them, selenoproteins have important antioxidant and detoxification functions. The interference in selenoprotein biosynthesis results in accumulation of ROS and consequently in a toxic intracellular environment. The resulting ROS imbalance can trigger apoptosis to eliminate the deleterious cells. In Drosophila, a null mutation in the selD gene (homologous to the human selenophosphate synthetase type 1) causes an impairment of selenoprotein biosynthesis, a ROS burst and lethality. We propose this mutation (known as selD(ptuf)) as a tool to understand the link between ROS accumulation and cell death. To this aim we have analyzed the mechanism by which selD(ptuf) mutant cells become apoptotic in Drosophila imaginal discs. The apoptotic effect of selD(ptuf) does not require the activity of the Ras/MAPK-dependent proapoptotic gene hid, but results in stabilization of the tumor suppressor protein Dmp53 and transcription of the Drosophila pro-apoptotic gene reaper (rpr). We also provide genetic evidence that the initiator caspase DRONC is activated and that the effector caspase DRICE is processed to commit selD(ptuf) mutant cells to death. Moreover, the ectopic expression of the inhibitor of apoptosis DIAP1 rescues the cellular viability of selD(ptuf) mutant cells. These observations indicate that selD(ptuf) ROS-induced apoptosis in Drosophila is mainly driven by the caspase-dependent Dmp53/Rpr pathway.