MST1 Promotes Apoptosis through Regulating Sirt1-dependent p53 Deacetylation
MST1 Promotes Apoptosis through Regulating Sirt1-dependent p53 Deacetylation
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MST1 通过调节 Sirt1 依赖性 p53 脱乙酰化促进细胞凋亡
DOI：
10.1074/jbc.m110.182543
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发表时间：
2011-03-04
影响因子：
4.8
通讯作者：
Yuan, Zengqiang
中科院分区：
文献类型：
--
作者：
Yuan, Fang;Xie, Qi;Yuan, Zengqiang
哺乳动物不育20-样蛋白激酶1(MST1)在多种应激诱导的细胞凋亡中起着重要作用。MST1是一种丝氨酸/苏氨酸激酶，在细胞凋亡刺激下被激活，进而激活其下游靶标JNK/p38、组蛋白H2B和FOXO。已有研究表明，MST1过表达通过激活P53而启动细胞凋亡。然而，在细胞凋亡过程中MST1-P53信号转导的分子机制尚不清楚。在这里，我们报告了MST1以P53依赖的方式促进遗传毒剂诱导的细胞凋亡。我们发现，MST1通过抑制Sirt1的去乙酰化及其与P53的相互作用来增加P53的乙酰化和反式激活，并且Sirt1可以被MST1磷酸化，从而抑制Sirt1的活性。综上所述，这些发现定义了一种新的调控机制，涉及MST1激酶对Sirt1的磷酸化，从而导致P53的激活，这对于我们理解DNA损伤诱导细胞凋亡的信号机制具有重要意义。
Mammalian Sterile 20-like kinase 1 (MST1) protein kinase plays an important role in the apoptosis induced by a variety of stresses. The MST1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, JNK/p38, histone H2B and FOXO. It has been reported that overexpression of MST1 initiates apoptosis by activating p53. However, the molecular mechanisms underlying MST1-p53 signaling during apoptosis are unclear. Here, we report that MST1 promotes genotoxic agent-induced apoptosis in a p53-dependent manner. We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity. Collectively, these findings define a novel regulatory mechanism involving the phosphorylation of Sirt1 by MST1 kinase which leads to p53 activation, with implications for our understanding of signaling mechanisms during DNA damage-induced apoptosis.