MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation |
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Authors: | Yuan Fang Xie Qi Wu Junbing Bai Yujie Mao Beibei Dong Yongli Bi Wenzhi Ji Guangju Tao Wufan Wang Yan Yuan Zengqiang |
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Affiliation: | State Key Laboratory of Brain and Cognitive Sciences, Chinese Academy of Sciences, Beijing 100101, China. |
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Abstract: | 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. |
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Keywords: | Apoptosis p53 Serine/Threonine Protein Kinase Signal Transduction SIRT |
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