Dataset Information

Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.

ABSTRACT:

Background & aims

Apoptosis mediated by p53 plays a pathological role in the progression of hepatosteatosis. It is noteworthy that p53 can promote the expression of damage-regulated autophagy modulator (DRAM), an inducer of autophagy-mediated apoptosis. However, the relationship between p53-mediated apoptosis and autophagy in hepatosteatosis remains elusive. This study aimed to examine how p53 orchestrates autophagy and apoptosis to affect hepatosteatosis.

Methods

HepG2 cells were treated with oleic acid (OA) for 24 h to induce hepatosteatosis. Mice were fed a high-fat diet for 20 or 40 weeks to induce hepatosteatosis.

Results

OA induced a dose-dependent increase in steatosis severity and apoptosis. OA also induced autophagy, which was a critical inducer of apoptosis in mild steatosis induced by 400 ?M OA, but not in the more severe steatosis induced by 800 and 1200 ?M OA. p53 inhibition by siRNA mostly blocked OA-induced apoptosis and autophagy. Moreover, OA-induced autophagy was DRAM-dependent and primarily occurred in the mitochondria (mitophagy), where DRAM was localized. In severe steatosis induced by 1200 ?M OA, apoptosis was mainly dependent on p53-induced expression of BAX, which was also localized to the mitochondria. Our in vivo study showed that p53 expression increased in both mild and severe hepatosteatosis. Increased DRAM expression and autophagy were identified in mild hepatosteatosis, whereas greater BAX expression was observed in severe hepatosteatosis.

Conclusions

p53 may induce apoptosis via different mechanisms. DRAM-mediated mitophagy is a primary apoptotic inducer in mild hepatosteatosis, whereas p53-induced BAX expression mainly induces apoptosis in severe hepatosteatosis.

SUBMITTER: Liu K

PROVIDER: S-EPMC4283711 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.

Liu Kai K Lou Jinli J Wen Tao T Yin Jiming J Xu Bin B Ding Wei W Wang Anna A Liu Daojie D Zhang Chao C Chen Dexi D Li Ning N

Liver international : official journal of the International Association for the Study of the Liver 20131101 10

<h4>Background & aims</h4>Apoptosis mediated by p53 plays a pathological role in the progression of hepatosteatosis. It is noteworthy that p53 can promote the expression of damage-regulated autophagy modulator (DRAM), an inducer of autophagy-mediated apoptosis. However, the relationship between p53-mediated apoptosis and autophagy in hepatosteatosis remains elusive. This study aimed to examine how p53 orchestrates autophagy and apoptosis to affect hepatosteatosis.<h4>Methods</h4>HepG2 cells were ...[more]

PMID: 23875779

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Project description:BACKGROUND:Studies link c-Abl activation with the accumulation of pathogenic ?-synuclein (?S) and neurodegeneration in Parkinson's disease (PD). Currently, c-Abl, a tyrosine kinase activated by cellular stress, is thought to promote ?S pathology by either directly phosphorylating ?S or by causing autophagy deficits. METHODS:?S overexpressing transgenic (Tg) mice were used in this study. A53T Tg mice that express high levels of human mutant A53T?S under the control of prion protein promoter. Two different approaches were used in this study. Natural aging and seeding model of synucleinopathy. In seeding model, intracortical/intrastriatal (IC/IS) stereotaxic injection of toxic lysates was done using tissue lysates from end-stage symptomatic mice. In this study, nilotinib and pifithrin-? was used as a c-Abl and p53 inhibitor, respectively. Both Tg and non-transgenic (nTg) mice from each group were subjected to nilotinib (10?mg/kg) or vehicle (DMSO) treatment. Frozen brain tissues from PD and control human cases were analyzed. In vitro cells study was implied for c-Abl/p53 genetic manipulation to uncover signal transduction. RESULTS:Herein, we show that the pathologic effects of c-Abl in PD also involve activation of p53, as c-Abl activation in a transgenic mouse model of ?-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Thus, we hypothesized that c-Abl-dependent p53 activation contributes to autophagy impairment in ?-synucleinopathy. In support of the hypothesis, we show that c-Abl activation is sufficient to inhibit autophagy in p53-dependent manner. Moreover, inhibition of either c-Abl, using nilotinib, or p53, using pifithrin-?, was sufficient to increase autophagic flux in neuronal cells by inducing phosphorylation of AMP-activated kinase (AMPK), ULK1 activation, and down-regulation of mTORC1 signaling. Finally, we show that pharmacological attenuation of c-Abl activity by nilotinib treatment in the TgA53T mouse model reduces activation of p53, stimulates autophagy, decreases accumulation ?S pathology, and delays disease onset. CONCLUSION:Collectively, our data show that c-Abl activation by ?-synucleinopathy causes p53 dependent autophagy deficits and both c-Abl and p53 represent therapeutic target for PD.

Dataset Information

Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.

Background & aims

Methods

Results

Conclusions

Publications

Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.

Similar Datasets

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