E-GEOD-44327
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA189474
PROVIDER: E-GEOD-44327 | ExpressionAtlas | 2025-01-24
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-44327-analysis-methods.tsv | Tabular | |||
| E-GEOD-44327-atlasExperimentSummary.Rdata | Rdata | |||
| E-GEOD-44327-configuration.xml | Xml | |||
| E-GEOD-44327-configuration.xml.beforeQC | Xml | |||
| E-GEOD-44327-percentile-ranks.tsv | Tabular |
Items per page: 5 1 - 5 of 59 |
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Project description:Activation of the hypoxia inducible transcription factor HIF-alpha and the NF-kappaB pathway promotes inflammation mediated tumor progression. The cellular transcription factor ZNF395 was repeatedly found over expressed in various human cancers and particularly in response to hypoxia, implying a functional relevance. To understand the biological activity of ZNF395, we identified target genes of ZNF395 by a genome-wide expression screen. Induced ZNF395 expression let to up-regulation of a subset of interferon (IFN)-responsive genes such as IFIT1/ISG56 and IFI44 as well as genes known to be involved in cancer progression including MEF2C and MACC1. ZNF395 requires its DNA binding domain and the two IFN-sensitive-response elements within the IFIT1/ISG56 promoter to activate. We provide evidence that IkBa kinase-mediated phosphorylation is required to allow activation of transcription by ZNF395 but simultaneously accelerates it for proteolytic degradation to keep the activity of ZNF395 transient and weak. We further confirm that ZNF395 is induced by hypoxia. Thus, two crucial pathways contributing to cancers progression, i.e. hypoxia and inflammation cooperate in activation of ZNF395 at the level of transcription and post-translational modification. Increased amounts of transcriptional active ZNF395 in cancers may support carcinogenesis by activating its target genes associated with the innate immune response and cancer. 4 samples treated with doxycycline-induced ZNF395 were compared to 4 untreated controls
2014-03-01 | E-GEOD-44327 | biostudies-arrayexpress
Project description:The hypoxia-inducible transcription factor ZNF395 is controlled by I-kappaB kinase and activates genes involved in the innate immune response and cancer
| PRJNA189474 | ENA
Project description:Activation of the hypoxia inducible transcription factor HIF-alpha and the NF-kappaB pathway promotes inflammation mediated tumor progression. The cellular transcription factor ZNF395 was repeatedly found over expressed in various human cancers and particularly in response to hypoxia, implying a functional relevance. To understand the biological activity of ZNF395, we identified target genes of ZNF395 by a genome-wide expression screen. Induced ZNF395 expression let to up-regulation of a subset of interferon (IFN)-responsive genes such as IFIT1/ISG56 and IFI44 as well as genes known to be involved in cancer progression including MEF2C and MACC1. ZNF395 requires its DNA binding domain and the two IFN-sensitive-response elements within the IFIT1/ISG56 promoter to activate. We provide evidence that IkBa kinase-mediated phosphorylation is required to allow activation of transcription by ZNF395 but simultaneously accelerates it for proteolytic degradation to keep the activity of ZNF395 transient and weak. We further confirm that ZNF395 is induced by hypoxia. Thus, two crucial pathways contributing to cancers progression, i.e. hypoxia and inflammation cooperate in activation of ZNF395 at the level of transcription and post-translational modification. Increased amounts of transcriptional active ZNF395 in cancers may support carcinogenesis by activating its target genes associated with the innate immune response and cancer.
2014-03-01 | GSE44327 | GEO
Project description:Hypoxia signaling induced by VHL deficiency fuels growth but also poses immense metabolic stress to clear cell renal cell carcinomas (ccRCCs). Tumor cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor alpha (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. We now show that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. ZNF395 is activated by a HIF2α-modulated super-enhancer but plays non-redundant functions from HIF2α. Specifically, ZNF395 facilitates the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2 (IDH2). Functionally, ZNF395 depletion results in reduced TCA intermediates and their derivatives, including amino acids, glutathione and pyrimidine nucleotides. In addition, ZNF395 depletion diminishes mitochondrial respiration; restoration of complex I function rescues the effects of ZNF395 depletion. Our study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
2024-10-01 | GSE247117 | GEO
Project description:Hypoxia signaling induced by VHL deficiency fuels growth but also poses immense metabolic stress to clear cell renal cell carcinomas (ccRCCs). Tumor cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor alpha (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. We now show that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. ZNF395 is activated by a HIF2α-modulated super-enhancer but plays non-redundant functions from HIF2α. Specifically, ZNF395 facilitates the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2 (IDH2). Functionally, ZNF395 depletion results in reduced TCA intermediates and their derivatives, including amino acids, glutathione and pyrimidine nucleotides. In addition, ZNF395 depletion diminishes mitochondrial respiration; restoration of complex I function rescues the effects of ZNF395 depletion. Our study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
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Project description:SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
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Project description:The tumor microenvironment (TME) typically includes hypoxic regions. Hypoxic cancer cells are resistant to many anti-neoplastic therapies and can seed recurrence; consequently, understanding how they survive could yield new therapeutic strategies. In response to decreasing oxygen, cells are known to successively activate hypoxia-inducible factor 1-alpha (HIF1alpha), endoplasmic reticulum (ER) stress, and AMP-dependent protein kinase (AMPK). We previously identified an additional pathway in which the protein-tyrosine phosphatase PTP1B (encoded by PTPN1) prevents the death of HER2+ breast cancer cells exposed to severe hypoxia (O2<1%) by inhibiting RNF213, a large (~600 kDa) E3 ubiquitin ligase containing two functional AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. These findings provided a potential explanation for earlier observations that Ptpn1-/- mice are resistant to Neu (rodent HER2)-induced breast cancer, but how PTP1B regulates RNF213, the identity(ies) of RNF213 targets, the mechanism of cell death, and the relevance to other RNF213 actions remained unclear. Via proximity-based proteomics, we identified the CYLD-SPATA2 complex, a major negative regulator of NF-kappaB activation, as an RNF213 substrate critical for hypoxia-induced cell death. Here we show that PTP1B and ABL1/2 reciprocally control the phosphorylation of RNF213 on Tyrosine-1275. Phosphorylation of this site promotes RNF213 oligomerization, resulting in RZ domain activation, LUBAC complex-dependent ubiquitylation and degradation of the CYLD/SPATA2 deubiquitinase complex, and NF-kappaB activation. NF-kappaB induces NLRP3 inflammasome priming, and concomitant hypoxia-induced ER stress triggers inflammasome activation, resulting in pyroptotic cell death. Mutagenesis experiments show that the RNF213 RING negatively regulates the RZ domain, and RING domain mutants, including those associated with MMD, catalyze LUBAC-independent CYLD/SPATA2 degradation. Our results identify a novel PTP1B/RNF213/CYLD/SPATA2 pathway responsible for the pyroptotic death of hypoxic tumor cells, reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders. The mass spectrometry raw files for the phosphorylation identification and proximity labeling results are included here.
2023-06-16 | MSV000092191 | MassIVE
Project description:Effects of innate immune stimuli on PAF1 knockout cells
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Project description:The abstract for the manuscript Inflammaging refers to low-grade, chronically activated innate immunity that negatively impacts adult survival. However, little is known about the intrinsic signaling pathway that upregulates innate immune genes during aging. Here using Drosophila melanogaster, we profile the microRNA targetomes in young and aged animals, and reveal Dawdle (Daw), an activin-like ligand of the TGF-beta pathway, as a physiological target of microRNA-252 (miR-252). We show that miR-252 cooperates with the transcriptional regulation of Daw by Forkhead box O (FoxO), a conserved transcriptional factor implicated in aging, at the post-transcriptional levels. Unopposed Daw triggers hyper activation of innate immune genes coupled with a catastrophic decline in organismal survival. Single-cell sequencing analysis describes a non-cell autonomous regulation between Daw and the induction of innate immune genes in the muscle. We further determine the downstream cascade by which Daw signaling leads to increased Kenny /IKKgamma protein, which in turn activates Relish/NF-kappaB protein and consequentially upregulation of innate immune genes. Finally, while aging leads to a decline in FoxO activity, transgenic increase of miR-252 and FoxO pathway factors in wild-type Drosophila extends lifespan and mitigates the induction of innate immune genes in aging. Together, we propose that miR-252 and FoxO repress inflammaging by cooperative inhibition of Daw mediated TGF-beta pathway.
2021-01-01 | GSE142655 | GEO
Project description:Genetics of gene expression across innate immune stimulation in primary monocytes
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