Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA304012 | ENA |
REPOSITORIES: ENA
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Project description:Formation of the Death-Inducing Signalling Complex (DISC) initiates the extrinsic apoptotic signalling cascade. Caspase-8 and its regulator cFLIP control death signalling by binding to the receptor via DISC-bound FADD. By elucidating the function of Caspase-10, a close homologue of caspase-8, we unexpectedly found that caspase-10 negatively regulates caspase-8-mediated cell death signalling in the DISC. We demonstrate that caspase-10 inhibits the activation of caspase-8 independent of cFLIP. Furthermore, we show that caspase-8 does not compete with other tandem DED proteins such as cFLIP or caspase-10 in binding via FADD to the receptor as current models suggest. By utilizing caspase-8 knockout cells, we demonstrate that caspase-8 has to be placed upstream of both cFLIP and caspase-10 in the DISC. We further show that DISC formation and/or stability depends on caspase-8 but is independent from its enzymatic activity. Surprisingly, we identified caspase-10 to rewire DISC-signalling to NF-kB activation and cell survival. Our data are consistent with a model in which caspase-10 and cFLIP co-ordinately regulate caspase-8-mediated cell death signalling.
2016-04-20 | GSE75365 | GEO
Project description:Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma
| PRJNA188236 | ENA
Project description:Recent studies have unveiled unexpected connections between cell death and cell motility involving caspases, key regulators of apoptosis. While traditionally recognized for their pro-apoptotic roles, caspases have emerged as regulators of physiological processes beyond cell death, including cellular differentiation and motility. In some particularly aggressive cancers like melanoma, caspase-3, a prominent executioner caspase, is unexpectedly and inexplicably highly expressed. Here, we describe a novel non-apoptotic role for caspase-3 in melanoma cell motility. Through comprehensive molecular and cellular analyses, we demonstrate that caspase-3 is constitutively associated with the cytoskeleton and crucially regulates melanoma cell migration and invasion in vitro and in vivo. Mechanistically, caspase-3 interacts with and modulates the activity of coronin1-B, a key regulator of actin polymerization, thereby promoting melanoma cell motility, independently of its apoptotic protease function. Furthermore, we identify specificity protein 1 (SP1) as a transcriptional regulator of CASP3 expression, and show that its inhibition reduces caspase-3 expression and impairs melanoma cell migration. Overall, this study provides insights into the multifaceted roles of caspase-3 in cancer progression, highlighting its relevance as a novel target for anti-metastatic therapies.
2024-07-03 | MSV000095228 | MassIVE
Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.
2013-03-13 | GSE43878 | GEO
Project description:It was previously shown that interferon defects in latently HIV infected cells make them permissive to MG1 mediated killing. To increase effectiveness of MG1 therapy, we have combined MG1 with the SMAC mimetic birinapant to increase MG1 mediated killing in latently infected J1.1 cells. Increased cell death was observed compared to either treatment alone and was accompanied by increased caspase-3/7 and caspase-1 expression. However, cell death could not be blocked by the pan-caspase inhibitor ZVAD-fmk or the necroptosis inhibitor necrostatin1-s, alone or in combination, indicating that cell death does not occur via a single pathway. Furthermore, it was shown that SMAC mimetic treatment results in decreased transcription of genes that take part in the immune signalling pathway, which is likely one the ways how SMAC mimetic treament senstizes HIV infected cells to MG1 mediated death.
2025-03-07 | GSE278469 | GEO
Project description:Recent studies have unveiled unexpected connections between cell death and cell motility involving caspases, key regulators of apoptosis. While traditionally recognized for their pro-apoptotic roles, caspases have emerged as regulators of physiological processes beyond cell death, including cellular differentiation and motility. In some particularly aggressive cancers like melanoma, caspase-3, a prominent executioner caspase, is unexpectedly and inexplicably highly expressed. Here, we describe a novel non-apoptotic role for caspase-3 in melanoma cell motility. Through comprehensive molecular and cellular analyses, we demonstrate that caspase-3 is constitutively associated with the cytoskeleton and crucially regulates melanoma cell migration and invasion in vitro and in vivo. Mechanistically, caspase-3 interacts with and modulates the activity of coronin1-B, a key regulator of actin polymerization, thereby promoting melanoma cell motility, independently of its apoptotic protease function. Furthermore, we identify specificity protein 1 (SP1) as a transcriptional regulator of CASP3 expression, and show that its inhibition reduces caspase-3 expression and impairs melanoma cell migration. Overall, this study provides insights into the multifaceted roles of caspase-3 in cancer progression, highlighting its relevance as a novel target for anti-metastatic therapies.
2025-10-07 | GSE270452 | GEO
Project description:The loss of functional caspase-10 promotes inflammatory cell death in macrophages and a fibrotic response of hepatic stellate cells, which may affect the pathogenesis of PBC.
2022-12-31 | GSE210070 | GEO
Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma. To generate a gene expression signature of caspase 10 signaling in multiple myeloma, cell lines (SKMM1 n=16, KMS12 n=8 and H929 n=12) were transduced with retroviral vectors expressing either shCasp10-2 or shCasp10-3. Similarly, lymphoma cell lines (OCI-Ly7 n=2 and OCI-Ly19 n=2) were transduced and used as a control. Following puromycin selection, shRNA expression was induced for 24 to 120 hours and gene expression was measured, comparing uninduced (Cy3) to induced (Cy5) cells, using lymphochip microarrays. Biological repeats were performed of H929 and SKMM1 samples.
2013-03-13 | E-GEOD-43878 | biostudies-arrayexpress
Project description:The non-canonical caspase-4/5 inflammasome has been only very recently characterized. It is expressed by macrophages, the principal effector cells of the innate immunity system, and is activated by gram-negative bacteria, ER stress, and UV radiation. Activation of this inflammasome results in pyroptosis, inflammatory cell death, and secretion of pro-inflammatory cytokines of the interleukin-1 family. In our model we transfected human primary macrophages with Lipopolysaccharide, a cell wall component of gram-negative bacteria, to simulate bacteria entering the cell and thus activating the caspase-4/5 inflammasome. We then performed high-throughput proteomics to identify proteins secreted during the stimulation. The secretome was separated into two fractions using size-exclusion centrifugation, with a 100 kDa cut-off we enriched extracellular vesicles (EVs) and the flow through was concentrated over 10 kDa to yield the rest-secretome (RS) samples. The EV and RS samples of LPS transfected cells were then compared to untreated cells.
2017-03-07 | PXD005083 | Pride
Project description:The non-canonical caspase-4/5 inflammasome has been only very recently characterized. It is expressed by macrophages, the principal effector cells of the innate immunity system, and is activated by gram-negative bacteria, ER stress, and UV radiation. Activation of this inflammasome results in pyroptosis, inflammatory cell death, and secretion of pro-inflammatory cytokines of the interleukin-1 family. In our model we transfected human primary macrophages with Lipopolysaccharide, a cell wall component of gram-negative bacteria, to simulate bacteria entering the cell and thus activating the caspase-4/5 inflammasome. We then performed high-throughput proteomics to identify proteins secreted during the stimulation. The secretome was separated into two fractions using size-exclusion centrifugation, with a 100 kDa cut-off we enriched extracellular vesicles (EVs) and the flow through was concentrated over 10 kDa to yield the rest-secretome (RS) samples. The EV and RS samples of LPS transfected cells were then compared to untreated cells.
2017-03-29 | MSV000080769 | MassIVE