PML is a ROS sensor activating p53 upon oxidative stress
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA392300 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
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.
| S-EPMC5679165 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-09-22 | GSE100617 | GEO
Project description:PML is a ROS sensor activating p53 upon oxidative stress
| PRJNA403838 | ENA
Project description:The Pml gene is essential to the formation of PML nuclear bodies, domains which have been associated with various functions such as apoptosis/senescence, DNA repair and cell proliferation( Lallemand-Breitenbach 2010). PML-NBs formation is regulated by cellular stress including oxidative stress(Jeanne 2010, de The 2012). To investigate the role of PML in ROS response in vivo, we analyse the expression difference betweem Pml wt and Pml KO under fasted condition, which easily up-regulate ROS in BALB/cByJ background
2017-09-22 | GSE100615 | GEO
Project description:The Pml gene is essential to the formation of PML nuclear bodies, domains which have been associated with various functions such as apoptosis/senescence, DNA repair and cell proliferation( Lallemand-Breitenbach 2010). PML-NBs formation is regulated by cellular stress including oxidative stress(Jeanne 2010, de The 2012). To investigate the role of PML in ROS response in vivo, we analyse the expression difference to the acetaminophen toxicity, which is initiated by ROS, in Pml wt and Pml KO mice.
2017-09-22 | GSE100616 | GEO
Project description:LARP7, a new ROS sensor, protects against heart failure by enhancing mitochondrial biogenesis
| PRJNA655954 | ENA
Project description:Clear cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia PML protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation, and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.
2024-04-23 | GSE246846 | GEO
Project description:The therapy-induced PML/RARA catabolism elicits the loss of APL-initiating cell self-renewal through PML NB reformation and P53 activation. These results explain the curative activity of the RA/arsenic combination, the resistance to RA of PLZF/RARA-driven APLs and they raise the prospect that activation of this PML/P53 checkpoint might have therapeutic values in other malignancies.
2014-01-11 | GSE51723 | GEO
Project description:The therapy-induced PML/RARA catabolism elicits the loss of APL-initiating cell self-renewal through PML NB reformation and P53 activation. These results explain the curative activity of the RA/arsenic combination, the resistance to RA of PLZF/RARA-driven APLs and they raise the prospect that activation of this PML/P53 checkpoint might have therapeutic values in other malignancies. Gene expression profiles of 36 transgenic induced APL and 36 viral transduction APL were hybridized using Affymetrix Mouse Gene 1.0 ST Arrays
2014-01-11 | E-GEOD-51723 | biostudies-arrayexpress