title: MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation.
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.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.forename: Junbing
authors.initials: J
authors.lastname: Wu
authors.forename: Yujie
authors.initials: Y
authors.lastname: Bai
authors.forename: Beibei
authors.initials: B
authors.lastname: Mao
authors.forename: Yongli
authors.initials: Y
authors.lastname: Dong
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Bi
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D045325:HCT116 Cells; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D056564:Sirtuin 1; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C082332:macrophage stimulating protein; C095566:STK4 protein, human; D000099317:Hippo Kinases; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse