Corbat2021 - Apoptotic Reaction Model.models
Ontology highlight
ABSTRACT:
SUBMITTER: 
Agustin
PROVIDER: MODEL2105210001 | BioModels | 2021-05-26
REPOSITORIES: BioModels
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Project description:Non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g. T790M) confer resistance to erlotinib. BMS-690514, a novel panHER/VEGFR inhibitor described here, exerted antiproliferative and pro-apoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation. In this model, BMS-690514 induced a G1 cell cycle arrest, as well as ultrastructural hallmarks of apoptosis, mitochondrial release of cytochrome c, and activation of caspases involved in the intrinsic (e.g. caspase -2, -3, -7 and -9), but not in the extrinsic (e.g. caspase-8) pathway. Caspase inhibition conferred partial protection against BMS-690514 cytotoxicity, pointing to the involvement of both caspase-dependent and -independent effector mechanisms. Transcriptome analyses revealed the upregulation of pro-apoptotic (e.g. Bim, Puma) and cell cycle inhibitory (e.g. p27Kip1, p57Kip2) factors, as well as the downregulation of anti-apoptotic (e.g. Mcl1), heat shock (e.g. HSP40, HSP70, HSP90) and cell cycle promoting (e.g. cyclins B1, D1 and D3, CDK1, MCM family proteins, PCNA) proteins. BMS-690514-induced death of H1975 cells was modified in a unique fashion by a panel of siRNAs targeting apoptosis modulators. Downregulation of components of the NF-kappaB survival pathway (e.g. p65, Nemo/IKK, TAB2) sensitized cells to BMS-690514, whereas knockdown of pro-apoptotic factors (e.g. Puma, Bax, Bak, caspase-2, etc) and DNA damage-related proteins (e.g. ERCC1, hTERT) exerted cytoprotective effects. BMS-690514 is a new pan-HER/VEGFR inhibitor that may become an alternative to erlotinib for the treatment of NSCLC.
2007-07-24 | E-TABM-239 | biostudies-arrayexpress
Project description:Cells can survive effector caspase (caspase 3/7) activation in response to transient apoptotic stimuli, a process named anastasis. To characterize the molecular events that occur during anastasis, we performed whole transcriptome RNA sequencing of untreated, apoptotic, and recovering cells. We found that anastasis is an active, two-stage program with unique transcriptional profiles in each stage. We also identified 10 genes that specific to the early stage of anastasis.
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Project description:TRAIL (TNF-Related Apoptosis Inducing Ligand) is a well-known apoptosis inducer, which activates the extrinsic death pathway. It is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by resistance which occurs in approximately 50% of cancer cells. SCFA (Short Chain Fatty Acids) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate/acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. We hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, boosted pro-apoptotic gene expression in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and on caspase-8, caspase-9 and caspase-3 activation, was more lethal on cancer cells than on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented only by P. freudenreichii induced apoptosis of HT29 cells and enhanced cytotoxic activity of TRAIL, as did P. freudenreichii culture supernatants or its metabolites SCFA. These results open new perspectives for the use of food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer.
2016-02-01 | GSE67033 | GEO
Project description:Different types of cell death, including apoptosis, play an important role in the immune defense of arthropods, as infected cells are eliminated, preventing the dissemination of the infectious agent throughout the animal body. The apoptosis can be triggered by two main pathways: the intrinsic or mitochondrial pathway and the extrinsic or death receptor pathway. Both culminate in the activation of the effector caspases, such as caspase-3, resulting, for instance in DNA fragmentation and exposition of markers on the surface of the apoptotic cell, allowing its recognition and elimination by phagocytic cells. To ensure survival and proliferation, microorganisms can inhibit apoptosis of the host cell. The differential proteome of a tick cell line (BME26) in response to an experimental infection with Rickettsia rickettsii, causative agent of the severe Rocky Mountain spotted fever, showed that pro-apoptotic proteins are downregulated in the beginning of infection (6 h) and upregulated in a later time-point (48 h). We therefore evaluated the effects of infection on classic features of apoptotic cells: the spontaneous fragmentation of gDNA and the activity of caspase-3 and the exposition of phosphatidylserine in BME26 cells after induction with staurosporine, a classic activator of apoptosis. The spontaneous fragmentation of DNA was observed exclusively in non-infected cells. In addition, the activity of caspase-3 and the exposition of phosphatidylserine is lower in infected than in non-infected cells. Caspase-3 activity is also lower in infected IBU/ASE-16 cells, an embryonic tick cell line of one primary vector of R. rickettsii in Brazil, Amblyomma sculptum. Importantly, while the activation of caspase-3 exerted a detrimental effect on rickettsial proliferation in BME26 cells, the enzyme inhibition increased bacterial growth. Together, our results suggest that R. rickettsii controls the apoptosis in tick cells, which seems to be important to ensure the colonization of the vector cell. To the best of our knowledge, this is the first report on the modulation of the apoptosis in a tick cell line upon the infection with a species of the genus Rickettsia.
2021-09-09 | PXD017942 | Pride
Project description:The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin d. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate LPS shock independent of caspase-8 or caspase-11. Both proteases had to be present to support tissue injury, dependent upon TNF and interferon , first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock, but collaborated to amplify the inflammatory signals associated with tissue injury. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independent of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization during inflammatory signaling in vivo where cytokines execute diverse cell death pathways and tissue damage.
2018-08-07 | GSE115094 | GEO
Project description:Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.
2016-09-15 | GSE86922 | GEO
Project description:Apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, thereby shaping the overall architecture of the gastrointestinal tract, but also regulating tolerance induction during homeostasis. To experimentally address this concept, we generated intestinal epithelial cell (IEC)-specific knockout mice that lack both executioner caspase-3 and caspase-7 (Casp3/7?IEC), which are the converging point of the extrinsic and intrinsic apoptotic pathway. Surprisingly, the overall architecture, cellular landscape and proliferation rate remained unchanged in these mice. However, non-apoptotic cell extrusion was increased in Casp3/7?IEC mice, compensating apoptosis deficiency, maintaining the same physiological level of IEC shedding. Microbiome richness and composition stayed unaffected, bearing no sign of dysbiosis. Transcriptome and single cell RNA sequences analyses of IECs and immune cells revealed no differences in signaling pathways of differentiation and inflammation. These findings demonstrate that during homeostasis apoptosis per se is dispensable for IEC turnover at the top of intestinal villi intestinal tissue dynamics, microbiome composition and immune regulation.
2021-09-22 | GSE183885 | GEO
Project description:Apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, thereby shaping the overall architecture of the gastrointestinal tract, but also regulating tolerance induction during homeostasis. To experimentally address this concept, we generated intestinal epithelial cell (IEC)-specific knockout mice that lack both executioner caspase-3 and caspase-7 (Casp3/7?IEC), which are the converging point of the extrinsic and intrinsic apoptotic pathway. Surprisingly, the overall architecture, cellular landscape and proliferation rate remained unchanged in these mice. However, non-apoptotic cell extrusion was increased in Casp3/7?IEC mice, compensating apoptosis deficiency, maintaining the same physiological level of IEC shedding. Microbiome richness and composition stayed unaffected, bearing no sign of dysbiosis. Transcriptome and single cell RNA sequences analyses of IECs and immune cells revealed no differences in signaling pathways of differentiation and inflammation. These findings demonstrate that during homeostasis apoptosis per se is dispensable for IEC turnover at the top of intestinal villi intestinal tissue dynamics, microbiome composition and immune regulation.
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Project description:Screening of lncRNAs involved in cancer cell evasion of extrinsic and intrinsic apoptotic pathways
| PRJNA490514 | ENA
Project description:This model is from the article:
Heterogeneity Reduces Sensitivity of Cell Death for TNF-Stimuli
Schliemann M, Bullinger E, Borchers S, Allgower F, Findeisen R, Scheurich P. BMC Syst Biol.
2011 Dec 28;5(1):204. 22204418
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Abstract:
BACKGROUND:
Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner.
RESULTS:
This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability.
CONCLUSIONS:
Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity.
Note:
SBML model generated from Matlab system description
on 12-July-2011 21:08:15 by
exportSBML Copyright Eric Bullinger 2007-2011
2012-01-16 | BIOMD0000000407 | BioModels