Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence
Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence
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DOI：
10.1093/emboj/21.10.2383
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发表时间：
2002-05-15
期刊：
影响因子：
11.4
通讯作者：
Kouzarides, T
中科院分区：
文献类型：
--
作者：
Langley, E;Pearson, M;Kouzarides, T
酵母 Sir2 蛋白通过内在的 NAD 依赖性组蛋白脱乙酰酶活性介导染色质沉默。 Sir2 是一种保守蛋白，最近被证明可以调节芽殖酵母和蠕虫的寿命延长。在这里，我们发现，在 PML 或致癌 Ras (Ha-rasV12) 过度表达后，SIRT1（人类 Sir2 同源物）被招募到哺乳动物细胞的早幼粒细胞白血病蛋白 (PML) 核体中。 SIRT1 结合 p53（PML 核体的一个组成部分）并使其去乙酰化，并且可以抑制 p53 介导的反式激活。此外，我们发现 SIRT1 和 p53 在 PML 上调时共定位于核体中。当在原代小鼠胚胎成纤维细胞 (MEF) 中过度表达时，SIRT1 会拮抗 PML 诱导的 p53 乙酰化并挽救 PML 介导的过早细胞衰老。综上所述，我们的数据表明 SIRT1 脱乙酰酶是 p53 功能的新型负调节因子，能够调节细胞衰老。
The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation. Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation. When over-expressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence. Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence.