SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization
SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization
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DOI：
10.1016/j.stem.2008.01.002
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发表时间：
2008-03-01
期刊：
影响因子：
23.9
通讯作者：
Broxmeyer, Hal E.
中科院分区：
文献类型：
--
作者：
Han, Myung-Kwan;Song, Eun-Kyung;Broxmeyer, Hal E.
核肿瘤抑制基因p53反式激活促凋亡基因或抗氧化基因，这取决于压力的严重程度，而细胞质p53诱导细胞依赖性凋亡没有基因反式激活。虽然SIRT 1，一种p53去乙酰化酶，抑制p53介导的反式激活，但SIRT 1如何调节这些p53多功能尚不清楚。在这里，我们表明，SIRT 1阻断细胞质p53的核转位，以响应内源性活性氧（ROS），并触发小鼠胚胎干细胞（mES）的细胞凋亡依赖。无抗氧化剂培养产生的ROS在野生型mES细胞中引起p53易位到线粒体中，但在SIRT 1（-/-）mES细胞中诱导p53易位到细胞核中。内源性ROS通过p53和BAX的线粒体转位触发野生型mES细胞凋亡，但抑制SIRT 1（-/-）mES的Nanog表达，表明SIRT 1使mES细胞对ROS敏感，并抑制p53介导的Nanog表达抑制。我们的研究结果表明，内源性活性氧控制是重要的mES细胞在培养中的维护。
Nuclear tumor suppressor p53 transactivates proapoptotic genes or antioxidant genes depending on stress severity, while cytoplasmic p53 induces mitochondrial-dependent apoptosis without gene transactivation. Although SIRT1, a p53 deacetylase, inhibits p53-mediated transactivation, how SIRT1 regulates these p53 multifunctions is unclear. Here we show that SIRT1 blocks nuclear translocation of cytoplasmic p53 in response to endogenous reactive oxygen species (ROS) and triggers mitochondrial-dependent apoptosis in mouse embryonic stem (mES) cells. ROS generated by antioxidant-free culture caused p53 translocation into mitochondria in wild-type mES cells but induced p53 translocation into the nucleus in SIRT1(-/-) mES cells. Endogenous ROS triggered apoptosis of wild-type mES through mitochondrial translocation of p53 and BAX but inhibited Nanog expression of SIRT1(-/-) mES, indicating that SIRT1 makes mES cells sensitive to ROS and inhibits p53-mediated suppression of Nanog expression. Our results suggest that endogenous ROS control is important for mES cell maintenance in culture.