Death-associated protein 3 regulates cellular senescence through oxidative stress response.
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.
Murata
Yoko
Y
Department of Mechanism of Aging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka-Cho, Obu-city, Aichi 474-8522, Japan.
Wakoh
Takeshi
T
Uekawa
Natsuko
N
Sugimoto
Masataka
M
Asai
Azusa
A
Miyazaki
Tadaaki
T
Maruyama
Mitsuo
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016922:Cellular Senescence; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000502:physiology; D041681:NIH 3T3 Cells; D018384:Oxidative Stress; D011506:Proteins / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C490762:Dap3 protein, mouse; D024101:Mitochondrial Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species