Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-44327
PROVIDER: PRJNA189474 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
2025-01-24 | E-GEOD-44327 | ExpressionAtlas
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: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.
2024-10-01 | GSE247116 | GEO
Project description:To test whether cholesterol overload in smooth muscle cells (SMCs) drives NF-kappaB signaling and to map target genes controlled by NF-kappaB signaling in SMCs, we cultured primary aortic SMCs from wildtype mice in the presence of cyclodextrin-complexed cholesterol or the prototypical NF-kappaB activator tumor necrosis factor (TNF) with or without blocking canonical NF-kappaB signaling by knockdown of inhibitor of kappaB kinase beta (Ikbkb).
2023-12-07 | E-MTAB-13416 | biostudies-arrayexpress
Project description:Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas. It is characterized by the presence of rare Hodgkin and Reed/Sternberg (HRS) cells embedded in an extensive inflammatory infiltrate. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in HRS cells which transcriptionally regulates expression of multiple anti-apoptotic factors and pro-inflammatory cytokines plays a central role in the pathogenesis of cHL (1, 2). In non-stimulated condition, NF-kappaB proteins are rendered inactive by binding to their inhibitors (IkappaB s), which sequester them in the cytoplasm. Stimulation of multiple receptors activates the IkappaB kinase (IKK) complex that phosphorylates IkappaB at two specific serine residues, followed by its ubiquitination and proteasomal degradation, thereby releasing NF-kappaB proteins and allowing their nuclear translocation (3). Recently, two studies provided further insights into the molecular mechanisms of IKK activation upon TNF stimulation (4, 5). Activation of the IKK complex and subsequent NF-kappaB activation requires Lys63 polyubiquitination of RIP1, a kinase which is recruited to the receptor upon TNF stimulation. IKK-gamma (NEMO), the regulatory subunit of the IKK complex, specifically recognizes these Lys63-linked polyubiquitins attached to RIP1 and thereby activates IKK and NF-kappaB (4, 5). A20 is an ubiquitin-modifying enzyme that inhibits NF-kappaB activation in succession of tumor necrosis factor (TNF) receptor and Toll-like receptor induced signals (6-8). This enzyme removes Lys63 linked ubiquitin chains from RIP1 and adds Lys48 polyubiquitins to RIP1, thereby targeting this factor for proteasomal degradation, thus explaining the molecular mechanism of NF-kappaB inhibition by A20 (6). A20 likely inhibits NF-kappaB acitivity also by additional means, including interaction with TRAF1 and TRAF2 (9).
2009-03-24 | GSE15264 | GEO
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:Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas. It is characterized by the presence of rare Hodgkin and Reed/Sternberg (HRS) cells embedded in an extensive inflammatory infiltrate. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in HRS cells which transcriptionally regulates expression of multiple anti-apoptotic factors and pro-inflammatory cytokines plays a central role in the pathogenesis of cHL (1, 2). In non-stimulated condition, NF-kappaB proteins are rendered inactive by binding to their inhibitors (IkappaB s), which sequester them in the cytoplasm. Stimulation of multiple receptors activates the IkappaB kinase (IKK) complex that phosphorylates IkappaB at two specific serine residues, followed by its ubiquitination and proteasomal degradation, thereby releasing NF-kappaB proteins and allowing their nuclear translocation (3). Recently, two studies provided further insights into the molecular mechanisms of IKK activation upon TNF stimulation (4, 5). Activation of the IKK complex and subsequent NF-kappaB activation requires Lys63 polyubiquitination of RIP1, a kinase which is recruited to the receptor upon TNF stimulation. IKK-ï§ï (NEMO), the regulatory subunit of the IKK complex, specifically recognizes these Lys63-linked polyubiquitins attached to RIP1 and thereby activates IKK and NF-kappaB (4, 5). A20 is an ubiquitin-modifying enzyme that inhibits NF-kappaB activation in succession of tumor necrosis factor (TNF) receptor and Toll-like receptor induced signals (6-8). This enzyme removes Lys63 linked ubiquitin chains from RIP1 and adds Lys48 polyubiquitins to RIP1, thereby targeting this factor for proteasomal degradation, thus explaining the molecular mechanism of NF-kappaB inhibition by A20 (6). A20 likely inhibits NF-kappaB acitivity also by additional means, including interaction with TRAF1 and TRAF2 (9). SNP 6.0 array (Affymetrix) analyses were performed according to the manufacturer's directions on DNA extracted from three Hodgkin cell lines (L1236, HDLM-2, U-HO1), HapMap samples included in the Genotyping Console Software 3.0 were used as references.
2010-05-20 | E-GEOD-15264 | biostudies-arrayexpress
Project description:The response to insufficient oxygen, termed hypoxia, is orchestrated by the conserved master regulator Hypoxia-Inducible Factor-1 (HIF-1), which is hyperactive in many cancers. Here, we describe a HIF-1 independent hypoxia response pathway controlled by Caenorhabditis elegans Nuclear Hormone Receptor NHR-49, an orthologue of mammalian lipid metabolism regulator Peroxisome Proliferator-Activated Receptor alpha (PPARα). nhr-49 is required for worm survival in hypoxia and is synthetically lethal with hif-1 in this context, demonstrating independent activity. RNA-seq data show that nhr-49 regulates a set of hif-1 independent hypoxia responsive genes, including autophagy genes that promote hypoxia survival. We further identified the Nuclear Hormone Receptor nhr-67 as a negative regulator and the Homeodomain-interacting Protein Kinase hpk-1 as a positive regulator in the NHR-49 pathway. Together, our experiments describe an essential hypoxia response pathway controlled by nhr-49 that includes new upstream and downstream components and is as important as hif-1 dependent hypoxia adaptation.
2022-03-16 | GSE166788 | GEO