mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in Psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells

Qi, Min; Zhou, Haiyan; Fan, Simiao; Zhao, Li; Yao, Guo‐Dong; Tashiro, Shin‐ichi; Onodera, Satoshi; Xia, Mingyu; Ikejima, Takashi

doi:10.1016/j.ejphar.2013.05.051

Cited by 26 publications

(24 citation statements)

References 43 publications

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“…In agreement with the effect of a redox stress on mTOR [12] we observed a de-phosphorylation of mTOR (Supplementary Figure S10) similar to the de-phosphorylation observed upon cells’ exposure to Torin. However, knock-down of caspase 3 protein expression did not prevent the decrease in phosphorylated mTOR following cells’ exposure to a sub-lethal oxidative stress (Supplementary Figure S11).…”

Section: Discussionsupporting

confidence: 90%

“…Of note, an increase in autophagy is crucial in maintaining normal cellular homeostasis and survival upon exposure to sub-lethal oxidative stress [10, 11]. The proposed mechanisms involved in the activation of autophagy by ROS include inhibition of mTOR activity [12], activation of extracellular regulated kinase (ERK) and/or c-Jun N-terminal kinase [13, 14], nuclear translocation of the high-mobility group box 1 Protein, as shown upon the activation of autophagy by Apogossypolone [15], increase in Beclin 1 expression, and inhibition of the cysteine protease Atg4 activity [16]. However, while these mechanisms mainly focus on the regulation of the formation of autophagic vacuoles, ROS have also been shown to affect lysosomes [17].…”

Section: Introductionmentioning

confidence: 99%

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Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway

et al. 2016

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Here we provide evidence to link sub-lethal oxidative stress to lysosome biogenesis. Exposure of cells to sub-lethal concentrations of exogenously added hydrogen peroxide resulted in cytosol to nuclear translocation of the Transcription Factor EB (TFEB), the master controller of lysosome biogenesis and function. Nuclear translocation of TFEB was dependent upon the activation of a cathepsin-caspase 3 signaling pathway, downstream of lysosomal membrane permeabilization and accompanied by a significant increase in lysosome numbers as well as induction of TFEB-dependent lysosome-associated genes expression such as Ctsl, Lamp2 and its spliced variant Lamp2a, Neu1, Ctsb, Sqstm1, and Atg9b. The effects of sub-lethal oxidative stress on lysosomal gene expression and biogenesis were rescued upon gene silencing of caspase 3 and TFEB. Notably, caspase 3 activation was not associated with phenotypic hallmarks of apoptosis, evidenced by the absence of caspase 3 substrate cleavage, such as PARP, Lamin A/C or gelsolin. Taken together, these data demonstrate for the first time an unexpected and non-canonical role of a cathepsin-caspase 3 axis in the nuclear translocation of TFEB leading to lysosome biogenesis under conditions of sub-lethal oxidative stress.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway

et al. 2016

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“…Phosphorylation of p53 on Ser15 (pS15-p53) following 1.5 mM H 2 O 2 treatment was in a time-dependent manner in COV434 cells (Figure 7B). JNK has been reported to be implicated in p53 accumulation [11]. Thus the effect of JNK on p53 was determined by JNK inhibitor.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma

et al. 2017

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Reactive oxygen species (ROS) play important roles in follicular development and survival. Granulosa cell death is associated with increased ROS, but the mechanism of granulosa cell death induced by ROS is not clear. In order to define the molecular link between ROS and granulosa cell death, COV434, human granulosa tumor cells, were treated with H2O2. Compared to control cells, H2O2 induced granulosa cell death in a dose- and time-dependent manner. H2O2 induced an increase in Bax, Bak and Puma, and a decrease in anti-apoptotic molecules such as Bcl-2, Bcl-xL and Mcl-1. Both knockdown of Puma and overexpression of Bcl-xL could inhibit H2O2-induced granulosa cell death. These results suggest that suppression of Puma and overexpression of anti-apoptotic Bcl-2 family members could improve granulosa cell survival. To explore the mechanisms responsible for these findings, ROS in granulosa cells treatment with H2O2 were measured. The results showed that ROS was increased in a H2O2 dose- and time-dependent manner at the earlier time point. In addition, H2O2 induced an increase in Nrf2 and phosphorylation of JNK and p53. SP600125, an inhibitor of JNK, inhibits H2O2-induced phosphorylation of JNK and p53, and granulosa cell death. Antioxidant N-acetylcysteine (NAC) dose-dependently prevents H2O2-induced granulosa cell death. Furthermore, NAC also prevents phosphorylation of JNK and p53 induced by H2O2. Taken together, these data suggest that H2O2 regulates cell death in granulosa cells via the ROS-JNK-p53 pathway. These findings provide an improved understanding of the mechanisms underlying granulosa cell apoptosis, which could potentially be useful for future clinical applications.

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“…Previous studies have shown that some chemotherapeutic agents could induce autophagy through the ROS-MAPKp53 pathways (Duan et al, 2011;Liu et al, 2009;Qi et al, 2013). We investigated whether the ROS-MAPK-p53 pathways played a role in the FTY720-induced autophagy, apoptosis and necrosis.…”

Section: Fty720 Activated the Ros-jnk-p53 Loop In Glioblastoma Cell Lmentioning

confidence: 99%

FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells

et al. 2015

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mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in Psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells

Cited by 26 publications

References 43 publications

Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway

Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway

Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma

FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells

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