Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA128083 | ENA |
REPOSITORIES: ENA
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Project description:Constitutively active RAS plays a central role in the development of skin cancer in the classical two stage skin carcinogenesis in mice and in a number of human cancers. Ras-mediated tumor formation is commonly associated with upregulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. MyD88 is a crucial intermediate in the expression of multiple innate immune responders through signaling from the Toll-like/IL-1R family. We report that mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis, and cultured MyD88-/- keratinocytes transduced with an oncogenic ras vector form only a few small tumors in orthotopic grafts. Initiated keratinocytes arising from oncogenic activation of ras are hyperproliferative but also resist signals for induced differentiation and upregulate a host of pro-inflammatory genes. Ras-transduced MyD88-/- keratinocytes are also hyperproliferative but the differentiation response is intact and pro-inflammatory genes are not upregulated. Using both genetic and pharmacological approaches, we find that in keratinocytes, the differentiation and immune regulation functions mediated by oncogenic ras require the establishment of an autocrine loop through IL-1α and its receptor leading to NF-κB activation. In the absence of MyD88 or IL-1R, this loop cannot be established. Further, blocking the IL-1a mediated NF-κB activation in ras-transduced wildtype keratinocytes corrects the defect in both differentiation response and proinflammatory gene expression. Collectively, these results demonstrate that ras activation converts normal keratinocytes to an initiated phenotype through a series of potentially reversible feedback signals that provide therapeutic opportunities through inhibition of IL-1 signaling. Gene expression comparison of wild type ras-transformed keratinocytes untreated (n=3) or treated (n=3) in vitro with the IL1R antagonist Anakinra.
2011-08-28 | E-GEOD-22777 | biostudies-arrayexpress
Project description:Constitutively active RAS plays a central role in the development of skin cancer in the classical two stage skin carcinogenesis in mice and in a number of human cancers. Ras-mediated tumor formation is commonly associated with upregulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. MyD88 is a crucial intermediate in the expression of multiple innate immune responders through signaling from the Toll-like/IL-1R family. We report that mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis, and cultured MyD88-/- keratinocytes transduced with an oncogenic ras vector form only a few small tumors in orthotopic grafts. Initiated keratinocytes arising from oncogenic activation of ras are hyperproliferative but also resist signals for induced differentiation and upregulate a host of pro-inflammatory genes. Ras-transduced MyD88-/- keratinocytes are also hyperproliferative but the differentiation response is intact and pro-inflammatory genes are not upregulated. Using both genetic and pharmacological approaches, we find that in keratinocytes, the differentiation and immune regulation functions mediated by oncogenic ras require the establishment of an autocrine loop through IL-1α and its receptor leading to NF-κB activation. In the absence of MyD88 or IL-1R, this loop cannot be established. Further, blocking the IL-1a mediated NF-κB activation in ras-transduced wildtype keratinocytes corrects the defect in both differentiation response and proinflammatory gene expression. Collectively, these results demonstrate that ras activation converts normal keratinocytes to an initiated phenotype through a series of potentially reversible feedback signals that provide therapeutic opportunities through inhibition of IL-1 signaling.
2011-08-29 | GSE22777 | GEO
Project description:We found that NB expression of TNFR2 and monocyte mTNFα are required for monocyte activation and IL-6 production, while NB TNFR1 and monocyte sTNFα are required for NB NF-κB activation. Treatment of NB-monocyte co-cultures with clinical-grade etanercept completely abrogated release of IL-6, G-CSF, IL-1α, and IL-1β and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNFα signaling in NB patients that relapsed.
2023-02-02 | GSE218915 | GEO
Project description:The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of several processes, but their role in inflammatory signaling and gene expression remains unclear. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression and the signaling pathways activating NF-κB and AP1. The knockdown of SIAH1/2 had no significant impact on IL-1α-induced activation of NF-κB and MAPK signaling pathways, but modulated the expression of approximately one third of IL-1α-regulated genes. Most of the proteins encoded by SIAH1/2-regulated genes form a regulatory network of proinflammatory factors. Thus SIAH1/2 proteins function as variable rheostats that control the amplitude of inflammatory gene expression.
2022-02-01 | GSE179190 | GEO
Project description:Cancer is a disease of aberrant intracellular signaling. The NF-κB family of transcription factors and the Ras family of small GTPases have emerged as particularly important mediators of the pro-proliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins, encoded by the genes Nkiras1 and Nkiras2, were previously shown to inhibit both NF-κB and Ras pathway activation through independent molecular mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In mice, each κB-Ras protein can compensate fully for loss of the other, making the functionally redundant in the context of Ras signaling. To understand the global effects of full κB-Ras deficiency in the context of Ras activation, we use microarray analysis to compare the transcriptome of MEFs lacking only κB-Ras 1 (Nkiras1-/- Nkiras2+/+, 1SKO) and MEFs lacking both isoforms of κB-Ras (Nkiras1-/- Nkiras2-/-, DKO) with and without EGF stimulation.
2023-10-16 | GSE216127 | GEO
Project description:EGFR targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. Activating Ras mutations are a negative prognostic factor for response to EGFR ablation therapy in multiple cancer types. Furthermore, the major adverse consequence of this therapy is an acneiform papulopustular eruption on normal skin. To better understand Ras signaling in an EGFR depleted environment, we performed gene expression profiling on oncogenic Ras transformed and wildtype mouse keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment. We were able to identify a 25 gene signature specific to the Ras-EGFR ablation interaction and a distinct 19 gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wildtype Ras reduces ontologies favoring cell cycle control and transcription while ablation in the context of oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. The study showed substantial differences in ontologies between chronic EGFR ablation and acute pharmacological ablation, both with and without Ras activation. Pathway and biochemical analysis indicates that activation of p38α is a response to both acute and chronic abrogation of EGFR signaling under conditions of Ras activation. This was confirmed in oncogenic RAS transformed human keratinocytes and in tumors developing in orthografts of EGFR ablated mouse keratinocytes transformed by oncogenic Ras. EGFR ablation in the absence of oncogenic Ras revealed Erk and IL-1β related pathways. These findings reveal previously unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy.
2012-01-11 | GSE29415 | GEO
Project description:Constitutive activation of the anti-apoptotic NF-κB signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 mutants in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-Catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-κB activation and promoted the stabilization of β-Catenin. Elevated β-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased β-Catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that β-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-κB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
2016-01-01 | GSE70025 | GEO
Project description:Persistent NF-κB activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Analysis of the cHL cell-secreted key factors for NF-κB activation by chromatography and subsequent mass spectrometry revealed lymphotoxin-α (LTA) as the causative factor for autocrine and paracrine activation of canonical and noncanonical NF-κB in cHL cell lines. Upon CRISPR/Cas9-mediated gene knockout of LTA in the cell line L-1236, we performed expression analysis of LTA knockout versus control cells by using the Affymetrix array, Clariom S human, profiling tool.
2019-05-22 | GSE131559 | GEO
Project description:Gastric mucosa responds to the pathogen Helicobacter pylori (H. pylori) by producing and release of pro-inflammatory cytokines that activate the innate immune system mainly through activation of the transcription factor NF-κB. Although NF-κB signaling is well studied for many possible inducers, induction by H. pylori remains poorly understood. Here, we performed a high-throughput genome-wide RNAi screen for genes influencing H. pylori-induced NF-κB activation. In comparison to TNFα or IL‐1β NF‐κB signaling, we identified 21 proteins unique necessary for H. pylori NF-κB pathway and 24 factors that inhibited the activation. Furthermore, we present here the R/Bioconductor package Nested Effect Model for systematic use in high-throughput screens to classify newly identified factors. We identified alpha kinase 1 (ALPK1) as particular important for the H. pylori NF‐κB pathway without affecting TNFα or IL‐1β signaling. ALPK1 silencing inhibits activity of TAK1 and the IκB kinases (IKKs), degradation of the NF‐κB inhibitor IκBα, nuclear translocation of the NF‐κB subunit p65, and transcription of the NF‐κB target genes, e.g. IL‐8. Thus, we identify ALPK1 as a novel inflammatory regulator functioning particularly in the NF‐κB signaling network activated by H. pylori.
2019-09-02 | GSE89613 | GEO
Project description:<p><strong>BACKGROUND:</strong> Cryopyrin-Associated Periodic Syndrome (CAPS) is an autoinflammatory condition consequence of monoallelic variants in the NLRP3 gene that exacerbate IL-1β production. These variants are gain-of-function, but the exact regulatory mechanism of the NLRP3 CAPS-inflammasome is not well yet understood. It is considered as a hypersensitive inflammasome triggered by cell priming, but patients with CAPS and animal disease models present inflammatory flares in the absence of external triggers.</p><p><strong>OBJECTIVES:</strong> To study the regulation and activation of the NLRP3 inflammasome in CAPS.</p><p><strong>METHODS:</strong> CAPS derived blood samples and genetically modified macrophages expressing different NLRP3 CAPS-associated variants were used to assess NLRP3 function dissociated from cell priming and cell metabolism.</p><p><strong>RESULTS:</strong> We found that CAPS-associated variants constitutively result in active NLRP3 inflammasomes, that induce a basal cleavage of gasdermin D, IL-18 release and pyroptosis. The constitutive active NLRP3 inflammasome was blocked by MCC950 and was dependent on NLRP3 expression level, being further regulated by deubiquitination. We also showed that activation of NF-κB with lipopolysaccharide or other endogenous host-derived molecules (palmitate, S100A9 or IL-6) further modulated the activation of the NLRP3 CAPS inflammasome and expanded the repertoire of molecules secreted from CAPS macrophages to IL-1β, IL-1α, HMGB1, cystatin B and the P2X7 receptor, identifying novel proteins involved in CAPS pathogenesis. NLRP3 inflammasomes with CAPS associated variants affected the immunometabolism of the myeloid compartment and impaired glycolysis.</p><p><strong>CONCLUSIONS:</strong> These findings demonstrate that NLRP3 CAPS-associated variants form a constitutive active inflammasome that induce basal pyroptosis and IL-18 release without cell priming, suggesting a priming-independent mechanism for the initiation of CAPS flares characterized with a profound affection in the immunometabolism.</p>
2024-01-09 | MTBLS7872 | MetaboLights