Death-associated protein 3 regulates cellular senescence through oxidative stress response
Death-associated protein 3 regulates cellular senescence through oxidative stress response
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DOI：
10.1016/j.febslet.2006.10.004
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发表时间：
2006-11-13
期刊：
影响因子：
3.5
通讯作者：
Maruyama, Mitsuo
中科院分区：
文献类型：
--
作者：
Murata, Yoko;Wakoh, Takeshi;Maruyama, Mitsuo
死亡相关蛋白3 （DAP3）最初被确定为细胞凋亡的积极介质。最近发现，DAP3主要定位于线粒体，这意味着它除了参与细胞凋亡外，还参与线粒体代谢的功能。然而，对DAP3这些生理功能的分子基础知之甚少。在这里，我们证明了DAP3在氧化应激诱导的复制性衰老和过早衰老中都减少，并且氧化应激诱导的DAP3减少主要在线粒体部分观察到。利用DAP3特异性短发夹RNA （shRNA）进行克隆生存实验，研究人员发现，DAP3的减少可诱导对氧化应激的抵抗，并减少细胞内活性氧（ROS）的产生。此外，该策略使我们能够证明DAP3的缺失与小鼠胚胎成纤维细胞（mef）的复制性衰老的避免有关。因此，我们的研究提供了线粒体DAP3参与细胞衰老的潜在调节功能的见解。(c) 2006年欧洲生化学会联合会。Elsevier B.V.版权所有。
Death-associated protein 3 (DAP3) has been originally identified as a positive mediator of apoptosis. It has been revealed recently that the predominant localization of DAP3 to mitochondria implies its functional involvement in mitochondrial metabolism in addition to apoptosis. However, little is known about the molecular basis of these physiological functions of DAP3. Here, we demonstrate that DAP3 is reduced in both replicative and premature senescence induced by oxidative stress, and the DAP3 reduction induced by oxidative stress is observed mostly in a mitochondrial fraction. Using DAP3-specific short hairpin RNA (shRNA) in a clonogenic survival assay, we reveal that reduction of DAP3 induces resistance to oxidative stress and decreases intracellular reactive oxygen species (ROS) production. Furthermore, this strategy allows us to show that loss of DAP3 is involved in the avoidance of replicative senescence in mouse embryonic fibroblasts (MEFs). Thus, our study offers an insight into the potential regulatory function of mitochondrial DAP3 involved in cellular senescence. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.