Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA147609 | ENA |
REPOSITORIES: ENA
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Project description:Deletion of HDAC1 induces caspase-independent autophagic cell death and mitotic defect in Hep3B cells
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Project description:Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma
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Project description:The receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (Raidd) functions as a dual adaptor protein due to its bipartite nature, and is therefore thought to be a constituent of different multiprotein complexes including the PIDDosome, where it connects the cell death-related protease, Caspase-2, with the p53-induced protein with a death domain 1 (Pidd1). As such, Raidd has been implicated in DNA-damage-induced apoptosis as well as in tumor suppression, the latter based on its role as a direct activator of Caspase-2, known to delay lymphomagenesis caused by overexpression of c-Myc or loss of ATM kinase. As loss of Caspase-2 leads to an acceleration of tumor onset in the Eµ-Myc mouse model we set out to interrogate the role of Raidd in this process in more detail. Our data obtained analyzing Eµ-Myc/Raidd-/- mice indicate that Raidd is unable to protect from c-MYC-driven lymphomagenesis. Similarly, we failed to observe an effect of Raidd-deficiency on thymic lymphomagenesis induced by y-irradiation or fibrosarcoma development driven by 3-methylcholanthrene. The role of Caspase-2 as a tumor suppressor can therefore be uncoupled from its ability to interact and auto-activate upon binding to Raidd. Further, we provide supportive evidence that the tumor suppressive role of Caspase-2 is related to maintaining genomic integrity and allowing efficient p53-mediated signaling. Overall, our findings suggest that Raidd, although described to be the key-adapter allowing activation of the tumor suppressor Caspase-2, fails to suppress tumorigenesis in vivo.
2015-01-14 | GSE64920 | GEO
Project description:The inflammatory functions of the cytokine tumor necrosis factor (TNF) rely on its ability to induce cytokine production and to induce cell death. Caspase dependent and independent pathways – apoptosis and necroptosis – respectively, regulate immunogenicity by the release of distinct sets of cellular proteins. To obtain an unbiased, systems-level understanding of this important process, we here applied mass spectrometry-based proteomics to dissect protein release during apoptosis and necroptosis. We report hundreds of proteins released from human myeloid cells in time-course experiments. Both cell death types induce receptor shedding, but only apoptotic cells released nucleosome components. Conversely, necroptotic cells release lysosomal components by activating lysosomal exocytosis at early stages of necroptosis- induced membrane permeabilisation and show reduced release of conventionally secreted cytokines.
2020-07-18 | PXD014966 | Pride
Project description:Human mutations in the death receptor Fas or its ligand FasL cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD â which mediate cell death downstream of Fas/FasL â cause severe immunodeficiency in addition to ALPS. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice significantly increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Illustrating the importance of this function of TNF in vivo, TNF blockade increased the mortality of mice infected with Streptococcus Pneumoniae, but did not do so when infected mice lacked N4BP1. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by Caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
2020-09-09 | GSE148066 | GEO
Project description:Human mutations in the death receptor Fas or its ligand FasL cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD â which mediate cell death downstream of Fas/FasL â cause severe immunodeficiency in addition to ALPS. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice significantly increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Illustrating the importance of this function of TNF in vivo, TNF blockade increased the mortality of mice infected with Streptococcus Pneumoniae, but did not do so when infected mice lacked N4BP1. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by Caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
2020-09-10 | GSE157786 | GEO
Project description:Caspase is best known as an enzyme involved in programmed cell death that is conserved in multicellular organisms. In addition to its role in cell death, caspase is emerging as an indispensable enzyme for a wide range of cellular functions, which have recently been termed as Caspase-Dependent non-lethal cellular Processes. We carefully examined the involvement of cell death signaling in tissue size determination using Drosophila wing as a model. We found that executioner caspase activity promoted wing growth independent of apoptosis. To identify the gene expression changes which account for the observed phenomena, we performed microarray analysis of wing imaginal disc upon caspase activity-inhibition by overexpressing p35. The analysis revealed the change in overall transcriptome, but not in the major tissue growth promoting signaling pathways.
2019-08-22 | GSE136170 | GEO
Project description:Caspase-1 from Human Myeloid Derived Suppressor Cells Can Promote T-cell independent Tumor Proliferation
| PRJNA447932 | ENA
Project description:Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune disease and IL-1R-dependent caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1R-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigated the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1/Ripk3/Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38-dependent Ripk1-independent IL-1 and TNF production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 MAP kinase activation to control TNF and IL-1α/β transcription, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and concomitant IL-1α/β release.
2019-11-12 | GSE139223 | GEO
Project description:The epigenetic modifier EZH2 is part of the polycomb repressive complex that suppresses gene expression via histone methylation. Activating mutations in EZH2 are found in a subset of melanoma that contributes to disease progression by inactivating tumor suppressor genes. In this study we have targeted EZH2 with a specific inhibitor (GSK126) or depleted EZH2 protein by stable shRNA knockdown. We show that inhibition of EZH2 has potent effects on the growth of both wild-type and EZH2 mutant human melanoma in vitro particularly in cell lines harboring the EZH2Y646 activating mutation. This was associated with cell cycle arrest, reduced proliferative capacity in both 2D and 3D culture systems, and induction of apoptosis. The latter was caspase independent and mediated by the release of apoptosis inducing factor (AIFM1) from mitochondria. Gene expression arrays showed that several well characterized tumor suppressor genes were reactivated by EZH2 inhibition. This included activating transcription factor 3 (ATF3) that was validated as an EZH2 target gene by ChIP-qPCR. These results emphasize a critical role for EZH2 in the proliferation and viability of melanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with melanoma. Tiffen JC, Gunatilake D, Gallagher SJ, Gowrishankar K, Heinemann A, Cullinane C, et al. Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. Oncotarget 2015;12:12
2019-11-15 | GSE140394 | GEO