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PML is a ROS sensor activating p53 upon oxidative stress

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE100617 | GEO | 2017/09/22

SECONDARY ACCESSION(S): PRJNA392300

REPOSITORIES: GEO

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PML is a ROS sensor activating p53 upon oxidative stress.

Project description:Promyelocytic leukemia (PML) nuclear bodies (NBs) recruit partner proteins, including p53 and its regulators, thereby controlling their abundance or function. Investigating arsenic sensitivity of acute promyelocytic leukemia, we proposed that PML oxidation promotes NB biogenesis. However, physiological links between PML and oxidative stress response in vivo remain unexplored. Here, we identify PML as a reactive oxygen species (ROS) sensor. Pml-/- cells accumulate ROS, whereas PML expression decreases ROS levels. Unexpectedly, Pml-/- embryos survive acute glutathione depletion. Moreover, Pml-/- animals are resistant to acetaminophen hepatotoxicity or fasting-induced steatosis. Molecularly, Pml-/- animals fail to properly activate oxidative stress-responsive p53 targets, whereas the NRF2 response is amplified and accelerated. Finally, in an oxidative stress-prone background, Pml-/- animals display a longevity phenotype, likely reflecting decreased basal p53 activation. Thus, similar to p53, PML exerts basal antioxidant properties but also drives oxidative stress-induced changes in cell survival/proliferation or metabolism in vivo. Through NB biogenesis, PML therefore couples ROS sensing to p53 responses, shedding a new light on the role of PML in senescence or stem cell biology.

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PML is a ROS sensor activating p53 upon oxidative stress

Project description:PML nuclear bodies (NBs) recruit partner proteins -including p53 and its regulators- controlling their abundance or function. Investigating arsenic sensitivity of acute promyelocytic leukemia, we proposed that PML oxidation promotes NB-biogenesis. Yet, physiological links between PML and oxidative stress response in vivo remain unexplored. Here we identify PML as a reactive oxygen species (ROS) sensor. Pml-/- cells accumulate ROS, while PML expression decreases ROS levels. Unexpectedly, Pml-/- embryos survive acute glutathione depletion. Moreover, Pml-/- animals are resistant to acetaminophen hepatotoxicity or fasting-induced steatosis. Molecularly, Pml-/- animals fail to properly activate oxidative stress-responsive p53 targets, while NRF2 response is accelerated. Finally, in an oxidative stress-prone background, Pml-/- animals display a longevity phenotype, likely reflecting decreased basal p53 activation. Thus, similar to p53, PML exerts basal anti-oxidant properties, but also drives oxidative stress-induced changes in cell survival/proliferation or metabolism in vivo. Through NB-biogenesis, PML therefore couples ROS-sensing to p53 responses, shedding a new light on PML role in senescence or stem cell biology.

2017-09-22 | GSE103642 | GEO

PML is a ROS sensor activating p53 upon oxidative stress

Project description:PML is a ROS sensor activating p53 upon oxidative stress

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Sirt3 is critical for p53-mediated ferroptosis upon ROS-induced stress.

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Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination.

Project description:Activating transcription factor 3 (ATF3) is rapidly induced by diverse environmental insults including genotoxic stress. We report herein that its interaction with p53, enhanced by genotoxic stress, stabilizes the tumor suppressor thereby augmenting functions of the latter. Overexpression of ATF3 (but not a mutated ATF3 protein (Delta102-139) devoid of its p53-binding region) prevents p53 from MDM2-mediated degradation and leads to increased transcription from p53-regulated promoters. ATF3, but not the Delta102-139 protein, binds the p53 carboxy-terminus and diminishes its ubiquitination and nuclear export. Genotoxic-stressed ATF3-null mouse embryonic fibroblasts, or cells in which ATF3 was reduced by small interference RNA, show inefficient p53 induction and impaired apoptosis compared with wild-type cells. ATF3-null cells (but not wild-type cells), which poorly accumulate p53, are transformed by oncogenic Ras. Thus, ATF3 is a novel stress-activated regulator of p53 protein stability/function providing the cell with a means of responding to a wide range of environmental insult, thus maintaining DNA integrity and protecting against cell transformation.

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Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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ARMS-NF-κB signaling regulates intracellular ROS to induce autophagy-associated cell death upon oxidative stress.

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MLL1 histone methyltransferase and UTX histone demethylase functionally cooperate to regulate the expression of NRF2 in response to ROS-induced oxidative stress

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2024-03-27 | GSE250128 | GEO

Non-thermal atmospheric pressure plasma preferentially induces apoptosis in p53-mutated cancer cells by activating ROS stress-response pathways.

Project description:Non-thermal atmospheric pressure plasma (NTAPP) is an ionized gas at room temperature and has potential as a new apoptosis-promoting cancer therapy that acts by generating reactive oxygen species (ROS). However, it is imperative to determine its selectivity and standardize the components and composition of NTAPP. Here, we designed an NTAPP-generating apparatus combined with a He gas feeding system and demonstrated its high selectivity toward p53-mutated cancer cells. We first determined the proper conditions for NTAPP exposure to selectively induce apoptosis in cancer cells. The apoptotic effect of NTAPP was greater for p53-mutated cancer cells; artificial p53 expression in p53-negative HT29 cells decreased the pro-apoptotic effect of NTAPP. We also examined extra- and intracellular ROS levels in NTAPP-treated cells to deduce the mechanism of NTAPP action. While NTAPP-mediated increases in extracellular nitric oxide (NO) did not affect cell viability, intracellular ROS increased under NTAPP exposure and induced apoptotic cell death. This effect was dose-dependently reduced following treatment with ROS scavengers. NTAPP induced apoptosis even in doxorubicin-resistant cancer cell lines, demonstrating the feasibility of NTAPP as a potent cancer therapy. Collectively, these results strongly support the potential of NTAPP as a selective anticancer treatment, especially for p53-mutated cancer cells.

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Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-08-24 | GSE71180 | GEO