SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis
SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis
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DOI：
10.1111/j.1365-2443.2010.01460.x
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发表时间：
2011-01-01
期刊：
影响因子：
2.1
通讯作者：
Inoue, Toshiaki
中科院分区：
文献类型：
--
作者：
Li, Yanze;Matsumori, Haruka;Inoue, Toshiaki
我们之前报道过sirtuin 2 (SIRT2)， NAD+依赖性蛋白去乙酰化酶的一个哺乳动物成员，参与有丝分裂调节，特别是纺锤体检查点引起的有效有丝分裂细胞死亡。在这里，我们描述了一种不同于有丝分裂调节的SIRT2的新功能。使用siRNA下调SIRT2可引起HeLa细胞等癌细胞系的凋亡，但在正常细胞中不发生凋亡。凋亡是由p53积累引起的，而p53积累是由p38 MAPK激活依赖性的p300降解和随后的MDM2降解介导的。Sirtuin抑制剂正在成为抗肿瘤药物，其功能归因于SIRT1的抑制，SIRT1是最具特征的Sirtuin，它能使p53去乙酰化以促进细胞存活，并在基因毒性应激下与其他蛋白质结合。本研究提示SIRT2可作为癌症治疗的新分子靶点，为SIRT2的疗效为未来癌症治疗提供分子基础。
We previously reported that sirtuin 2 (SIRT2), a mammalian member of the NAD+-dependent protein deacetylases, participates in mitotic regulation, specifically, in efficient mitotic cell death caused by the spindle checkpoint. Here, we describe a novel function of SIRT2 that is different from mitotic regulation. SIRT2 down-regulation using siRNA caused apoptosis in cancer cell lines such as HeLa cells, but not in normal cells. The apoptosis was caused by p53 accumulation, which is mediated by p38 MAPK activation-dependent degradation of p300 and the subsequent MDM2 degradation. Sirtuin inhibitors are emerging as antitumor drugs, and this function has been ascribed to the inhibition of SIRT1, the most well-characterized sirtuin that deacetylases p53 to promote cell survival and also binds to other proteins in response to genotoxic stress. This study suggests that SIRT2 can be a novel molecular target for cancer therapy and provides a molecular basis for the efficacy of SIRT2 for future cancer therapy.