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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.

SUBMITTER: Yuan F

PROVIDER: S-EPMC3044949 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation.

Yuan Fang F Xie Qi Q Wu Junbing J Bai Yujie Y Mao Beibei B Dong Yongli Y Bi Wenzhi W Ji Guangju G Tao Wufan W Wang Yan Y Yuan Zengqiang Z

The Journal of biological chemistry 20110106 9

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 MS ...[more]

PMID: 21212262

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Project description:Cardiomyocyte inflammation followed by apoptosis and fibrosis is an important mediator for development and progression of heart failure. Activation of toll-like receptor 4 (TLR4), an important regulator of inflammation, causes the progression of cardiac hypertrophy and injury. However, the precise mechanism of TLR4-mediated adverse cardiac outcomes is still elusive. The present study was designed to find the role of TLR4 in cardiac fibrosis and apoptosis, and molecular mechanism thereof. Rats were treated with TLR4 agonist (LPS 12.5 μg/kg/day) through osmotic pump for 14 days. To simulate the condition in vitro, H9c2 cells were treated with LPS (1 μg/ml). Similarly, H9c2 cells were transfected with TLR4 and SIRT2 c-DNA clone for overexpression. Myocardial oxidative stress, inflammation, fibrosis and mitochondrial parameters were evaluated both in vitro and in vivo. Cardiac inflammation after LPS treatment was confirmed by increased TNF-α and IL-6 expression in rat heart. There was a marked increase in oxidative stress as observed by increased TBARS and decreased endogenous antioxidants (GSH and catalase), along with mitochondrial dysfunction as measured by mitochondrial complex activity in LPS-treated rat hearts. Histopathological examination showed the presence of cardiac fibrosis after LPS treatment. Protein expression of nuclear p53 and cleaved caspase-7/caspase-9 was significantly increased in LPS treated heart. Similar to in vivo study, nuclear translocation of p53, mitochondrial dysfunction and cellular apoptosis were observed in H9c2 cells treated with LPS. Our data also indicate that decreased expression of SIRT2 was associated with increased acetylation of p53 after LPS treatment. In conclusion, TLR4 activation in rats promotes cardiac inflammation, mitochondrial dysfunction, apoptosis and fibrosis. p53 and caspase 7/caspase 9 were found to play an important role in TLR4-mediated apoptosis. Our data suggest that, reducing TLR4 mediated fibrosis and apoptosis could be a novel approach in the treatment of heart failure, keeping in the view the major role played by TLR4 in cardiac inflammation.

Project description:MicroRNA (miR)-874-3p is a newly identified miRNA that is involved in several pathological processes, including cancer, myocardial infarction, bone formation and erectile dysfunction. However, the role of miR-874-3p in polycystic ovary syndrome (PCOS) and granulosa cell (GC) apoptosis is not completely understood. The present study investigated the expression profile of miR-874-3p in PCOS by reverse transcription- quantitative PCR and the GC apoptosis by flow cytometry analysis. miR-874-3p expression was significantly upregulated in GCs isolated from patients with PCOS compared with patients without PCOS. In addition, miR-874-3p expression was positively correlated with GC apoptosis and testosterone levels in both patients with PCOS and patients without PCOS. Therefore, the present study also aimed to investigate the effects of miR-874-3p on testosterone-induced GC apoptosis. Compared with vehicle-treated GCs, miR-874-3p expression levels were significantly increased in testosterone-treated GCs, which was inhibited by the androgen receptor antagonist flutamide. GCs were transfected with either the miR-874-3p mimic or a miR-874-3p inhibitor. Compared with the control group, miR-874-3p mimic significantly enhanced GC apoptosis, whereas miR-874-3p inhibitor significantly decreased GC apoptosis. Moreover, histone deacetylase (HDAC) activity and HDAC1 expression levels were decreased in testosterone-treated GCs compared with vehicle-treated GCs. HDAC1 overexpression significantly attenuated the proapoptotic effects of testosterone. Additionally, miR-874-3p mimic and inhibitor significantly decreased and increased HDAC1 expression levels, respectively, compared with the control group. miR-874-3p inhibitor failed to attenuate HDAC1 overexpression-induced GC apoptosis. Furthermore, compared with the control group, testosterone treatment notably increased p53 expression and acetylation. Compared with the control group, western blotting analysis showed that miR-874-3p mimic notably increased p53 expression and acetylation, whereas miR-874-3p inhibitor markedly decreased p53 expression and acetylation. However, miR-874-3p inhibitor did not further decrease p53 acetylation and expression in cell overexpressing HDAC1. Collectively, the results of the present study indicated that miR-874-3p was upregulated in PCOS and promoted testosterone-induced GC apoptosis by suppressing HDAC1-mediated p53 deacetylation. Therefore, the present study improved the current understanding of the pathogenesis of PCOS and GC apoptosis.

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MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation.

Publications

MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation.

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