Homo sapiens
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PROVIDER: PRJNA230747 | ENA |
REPOSITORIES: ENA
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Project description:FOXO transcription factors control cellular formation of reactive oxygen species (ROS), which critically contribute to cell survival and cell death in neuroblastoma. Here, we report that C10orf10, also named M-bM-^@M-^\Decidual Protein induced by Progesterone (DEPP)M-bM-^@M-^], is a direct transcriptional target of FOXO3 in human neuroblastoma. As FOXO3-mediated apoptosis involves a biphasic ROS accumulation, we analyzed cellular ROS levels in DEPP-knockdown cells by live-cell imaging. Knockdown of DEPP prevented the primary and secondary ROS accumulation during FOXO3 activation and attenuates FOXO3-induced apoptosis, whereas its overexpression raises cellular ROS levels and sensitizes to cell death. In neuronal cells, cellular steady state ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that enables protein import into peroxisomes, we analyzed the effect of DEPP on peroxisomal function by measuring the catalase enzyme activity. Catalase activity was reduced by conditional DEPP overexpression and significantly increased in DEPP-knockdown cells. Using live cell imaging and fluorescent peroxisomal and mitochondrial probes we demonstrate that DEPP localizes to peroxisomes and mitochondria in neuroblastoma cells. The combined data indicate that DEPP reduces peroxisomal activity and thereby impairs the cellular ROS detoxification capacity and contributes to death sensitization. SH-EP, NB15 neuroblastoma cells and CCRF-CEM-C7H2 acute lymphoblastic leukemia cells were infected with the retrovirus plasmid pLIB-FOXO3(A3)-Ertm-iresNeo. Gene expression measures of samples with activated FOXO3 transcription factor (3h OHT treated) have been compared to untreated samples (0h time point). To rule out gene regulations by estrogen samples treated for 3 hours with tamoxifen have been compared to the untreated samples. Only genes that were more than two-fold regulated in the first, but not in the second comparison were defined to be FOXO3 regulated.
2014-10-06 | E-GEOD-53046 | biostudies-arrayexpress
Project description:FOXO transcription factors control cellular formation of reactive oxygen species (ROS), which critically contribute to cell survival and cell death in neuroblastoma. Here, we report that C10orf10, also named “Decidual Protein induced by Progesterone (DEPP)”, is a direct transcriptional target of FOXO3 in human neuroblastoma. As FOXO3-mediated apoptosis involves a biphasic ROS accumulation, we analyzed cellular ROS levels in DEPP-knockdown cells by live-cell imaging. Knockdown of DEPP prevented the primary and secondary ROS accumulation during FOXO3 activation and attenuates FOXO3-induced apoptosis, whereas its overexpression raises cellular ROS levels and sensitizes to cell death. In neuronal cells, cellular steady state ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that enables protein import into peroxisomes, we analyzed the effect of DEPP on peroxisomal function by measuring the catalase enzyme activity. Catalase activity was reduced by conditional DEPP overexpression and significantly increased in DEPP-knockdown cells. Using live cell imaging and fluorescent peroxisomal and mitochondrial probes we demonstrate that DEPP localizes to peroxisomes and mitochondria in neuroblastoma cells. The combined data indicate that DEPP reduces peroxisomal activity and thereby impairs the cellular ROS detoxification capacity and contributes to death sensitization. SH-EP, NB15 neuroblastoma cells and CCRF-CEM-C7H2 acute lymphoblastic leukemia cells were infected with the retrovirus plasmid pLIB-FOXO3(A3)-Ertm-iresNeo.
2014-10-06 | GSE53046 | GEO
Project description:N6-methyladenosine (m6A) is a type of nucleotide modification abundant in mRNA, which regulates mRNA stability, splicing and translation. However, its physiological role in intratumoral microenvironment and drug resistancehave not been fully understood. We demonstrated that METTL3,a primary m6A methyltransferase, was significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promoted sorafenib-resistance and angiogenesis and exacerbated progression by activating autophagy-associated pathway. Mechanistically, we identified FOXO3 as a key downstream target of the METTL3-mediated m6A modification. The m6A modification of FOXO3 at the 3'-untranslated region increased FOXO3 mRNA stability. Analysis of clinical samples showed that METTL3levels aretightly correlated with FOXO3levels in patients with HCC, and suppression of FOXO3 predicted poor clinical outcomes. Importantly, METTL3-depletion significantly enhanced sorafenib-resistance of HCC via a METTL3-FOXO3 axis, whereasoverexpression of FOXO3 restored the m6A-dependent sorafenib-sensitivity. Collectively, our work revealedthe critical function of the METTL3-mediated m6A modification in HCC in hypoxic tumor microenvironment, and provided insights into the molecular mechanism of the m6A modification in the resistance of HCC to sorafenib therapy.
2020-04-03 | GSE143234 | GEO
Project description:N6-methyladenosine (m6A) is a type of nucleotide modification abundant in mRNA, which regulates mRNA stability, splicing and translation. However, its physiological role in intratumoral microenvironment and drug resistancehave not been fully understood. We demonstrated that METTL3,a primary m6A methyltransferase, was significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promoted sorafenib-resistance and angiogenesis and exacerbated progression by activating autophagy-associated pathway. Mechanistically, we identified FOXO3 as a key downstream target of the METTL3-mediated m6A modification. The m6A modification of FOXO3 at the 3'-untranslated region increased FOXO3 mRNA stability. Analysis of clinical samples showed that METTL3levels aretightly correlated with FOXO3levels in patients with HCC, and suppression of FOXO3 predicted poor clinical outcomes. Importantly, METTL3-depletion significantly enhanced sorafenib-resistance of HCC via a METTL3-FOXO3 axis, whereasoverexpression of FOXO3 restored the m6A-dependent sorafenib-sensitivity. Collectively, our work revealedthe critical function of the METTL3-mediated m6A modification in HCC in hypoxic tumor microenvironment, and provided insights into the molecular mechanism of the m6A modification in the resistance of HCC to sorafenib therapy.
2020-04-03 | GSE143233 | GEO
Project description:FOXO transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into mechanisms of FOXO regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. Paper with published gene expression: PMID 22139133. Examination of FOXO3 binding and changes in RNAPII occupancy (0, 4, 24 hours after induction) in colorectal cell line
2012-11-15 | E-GEOD-35486 | biostudies-arrayexpress
Project description:Although light is essential for photosynthesis, it has the potential to elevate intracellular levels of reactive oxygen species (ROS). Since high ROS levels are cytotoxic, plants must alleviate such damage. However, the cellular mechanism underlying ROS-induced leaf damage alleviation in peroxisomes was not fully explored. Here, we show that autophagy plays a pivotal role in the selective removal of ROS-generating peroxisomes, which protects plants from oxidative damage during photosynthesis. We present that autophagy-deficient mutants show light intensity-dependent leaf damage and excess aggregation of ROS-accumulating peroxisomes. The peroxisome aggregates are specifically engulfed by pre-autophagosomal structures and vacuolar membranes in both leaf cells and isolated vacuoles, but they are not degraded in mutants. ATG18a-GFP and GFP-2×FYVE, which bind to phosphatidylinositol 3-phosphate, preferentially target the peroxisomal membranes and pre-autophagosomal structures near peroxisomes in ROS-accumulating cells under high-intensity light. Our findings provide deeper insights into the plant stress response caused by light irradiation.
2023-02-27 | PXD038480 | Pride
Project description:FOXO transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into mechanisms of FOXO regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. Paper with published gene expression: PMID 22139133.
2012-11-15 | GSE35486 | GEO
Project description:Forkhead Box O (FoxO) transcription factors are conserved proteins involved in the regulation of life span and age-related diseases, such as diabetes and cancer. Stress stimuli or growth factor deprivation promote nuclear localization and activation of FoxO proteins, which - depending on the cellular context - leads to cell cycle arrest or apoptosis. Moreover, FoxOs can control oxidative stress resistance and cell metabolism. In endothelial cells (ECs), they additionally regulate angiogenesis and may promote inflammation and vessel destabilization implicating a role of FoxOs in vascular diseases. In several cancers, FoxO transcription factors exert a tumor-suppressive function, due to their critical role in regulating proliferation and survival. Others and we have previously shown that FoxOs can regulate these processes via two different mechanisms: either by direct binding to FoxO-responsive elements (FRE) at the promoter of target genes or by a poorly understood alternative process that does not require direct DNA binding and regulates key targets in primary human ECs. Here we performed an interaction study in ECs to identify new nuclear FoxO3 interaction partners, which might contribute to FoxO-dependent gene regulation. Mass spectrometry analysis of FoxO3-interacting proteins revealed Transformation/Transcription Domain-Associated Protein (TRRAP), a member of multiple histone acetyltransferase (HAT) complexes, as novel binding partner of FoxO family proteins. TRRAP is required to support FoxO3 transactivation and FoxO3-dependent apoptosis in ECs via transcriptional activation of the proapoptotic Bcl-2 family member BIM. Moreover, FoxO-TRRAP interaction might explain FoxO-induced alternative gene regulation via TRRAP-dependent recruitment to target promoters lacking FRE sequences.
2022-01-20 | PXD027615 | Pride
Project description:MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to ROS augmenting agents
| PRJNA384369 | ENA
Project description:In the nervous system, neural stem cells (NSC) are necessary for the generation of new neurons and for cognitive function. Here we show that FoxO3, a member of a transcription factor family known to extend lifespan in invertebrates, regulates the NSC pool. We find that adult FoxO3-/- mice have fewer NSC in vivo than wild type counterparts. NSC isolated from adult FoxO3-/- mice have decreased self-renewal and an impaired ability to generate different neural lineages. Identification of the FoxO3-dependent gene expression profile in NSC suggests that FoxO3 regulates the NSC pool by inducing a program of genes that preserves quiescence, prevents premature differentiation, and controls oxygen metabolism. The ability of FoxO3 to prevent the premature depletion of NSC might have important implications for counteracting brain aging in long-lived species. Experiment Overall Design: mRNA expression from secondary neurospheres cultured from cells taken from mouse forebrains was compared between FoxO3+/+ (wildtype) and FoxO3-/- (null mutant) mice from the FVB/N background.
2009-12-05 | E-GEOD-18326 | biostudies-arrayexpress