The precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16
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PROVIDER: PRJNA646217 | ENA |
REPOSITORIES: ENA
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Project description:Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and higher rates of mortality. Anti-aging targeted small molecule screens have been carried outperformed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an conserved metabolite through eEukaryotes-conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggestsed that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. However, the mechanism study shows itslongevity effects could be fully blocked by a null-allele mutation of the tumor suppressor gene, daf-18 (homologous to mouse Pten), areand was independent of its classical pathway downstream elements, akt or daf-16., but Instead, we found MI effects on aging were dependent on its downstream mitophagy regulator pink-1. MI’s anti-aging effect is was also conserved in mouse model, implicatingindicating a conserved mechanism in mammals that may extend to human.
2020-08-03 | GSE154417 | GEO
Project description: Not available
| S-EPMC7479145 | biostudies-literature
Project description:Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility and premature aging. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with aging. Here we show that the FoxO transcription factor DAF-16 is activated in response to DNA damage during development while the DNA damage responsiveness of DAF-16 declines with aging. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA damage induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16 mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists. Synchronized L1 and mutant larvae were UV or mock treated, or starved. Mock treated samples served as controls for both the UV-treated and starved groups.
2014-11-18 | E-GEOD-51162 | biostudies-arrayexpress
Project description:Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility and premature aging. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with aging. Here we show that the FoxO transcription factor DAF-16 is activated in response to DNA damage during development while the DNA damage responsiveness of DAF-16 declines with aging. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA damage induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16 mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists.
2014-11-18 | GSE51162 | GEO
Project description:Phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) is a lipid second messenger produced by class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2). Although typically associated with the plasma membrane, it is now appreciated that PI(3,4,5)P3 generation also occurs in the nucleus to regulate a variety of biological functions. Using a PI(3,4,5)P3-specific GST-GRP1PH domain reporter and immunofluorescence microscopy, we have found that DLD1 and SW480 colorectal cancer (CRC) cells exhibit pronounced nuclear staining of PI(3,4,5)P3. To characterise the nuclear PI(3,4,5)P3 interactome in DLD1 and SW480 cells, we performed affinity pull-down experiments on nuclear extracts using a ω-amino analogue of phosphatidylinositol 3,4,5 -triphosphate (PI(3,4,5)P3 immobilised onto Affi-gel10 beads. Gel fractionation and LC/MS-MS analysis was performed to reduce sample complexity and increase resolution, with samples run on a LTQ Orbitrap Elite mass spectrometer. DLD1 and SW480 cells were both analysed in four independent biological replicates. A protein was considered a member of the nuclear PI(3,4,5)P3 interactome if it was identified in at least two experiments (with at least two peptides, FDR of 1%) in both cell lines, yielding a total of 1237 unique proteins (representing 1103 genes for DLD1 and 1001 genes for SW480 cells).
2023-05-10 | PXD021936 | Pride
Project description: Not available
| S-EPMC5813967 | biostudies-literature
Project description:Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility and premature aging. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with aging. Here we show that the FoxO transcription factor DAF-16 is activated in response to DNA damage during development while the DNA damage responsiveness of DAF-16 declines with aging. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA damage induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16 mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists. Synchronized L1 and xpa-1 mutant larvae were UV or mock treated, or starved
2014-11-18 | E-GEOD-51161 | biostudies-arrayexpress
Project description:total RNA from N2, daf-1(m40), and daf-1(m40);daf-3(mgDf90) adult, gravid hermaphrodites were extracted and sequenced.
2020-05-28 | GSE131997 | GEO
Project description:Under adverse environmental conditions, nematodes arrest into dauer, an alternative developmental stage for diapause. Dauers endure unfavorable environment and interact with host animals to access favorable environments, thus playing a critical role in the survival of both free-living and parasitic nematodes. Here, we discovered that in Caenorhabditis elegans, daf-42 is essential for development into dauer stage, as the null mutant shows lethal phenotype during dauer entry. To examine the transcriptional changes accompanied by the absence of DAF-42 during dauer entry, we performed RNA-sequencing on daf-2 and daf-2; daf-42 worms at 52 hours after egg laying (HAE) and 60 HAE, the time at which 0% and about 40% of daf-2; daf-42 mutants form dead dauer at 25 degrees Celcius, respectively. daf-2 control worms develop into dauer stage after 60 HAE, and half of its population develop into dauer by 72 HAE, when raised at 25 degrees Celcius.
2023-04-23 | GSE230353 | GEO
Project description:Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility and premature aging. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with aging. Here we show that the FoxO transcription factor DAF-16 is activated in response to DNA damage during development while the DNA damage responsiveness of DAF-16 declines with aging. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA damage induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16 mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists.
2014-11-18 | GSE51161 | GEO