Caspase-10 affects PBC pathogenesis
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ABSTRACT:
PROVIDER: PRJNA863615 | 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:Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis, is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. As CD4+ T cells play a pivotal role in immunological dysfunction observed in PBC, we analyzed microRNA(miRNA) and mRNA expression in CD4+ T cells to investigate PBC pathogenesis and identify novel therapeutic targets.
2017-01-06 | GSE93171 | GEO
Project description:Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis, is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. As CD4+ T cells play a pivotal role in immunological dysfunction observed in PBC, we analyzed microRNA(miRNA) and mRNA expression in CD4+ T cells to investigate PBC pathogenesis and identify novel therapeutic targets.
2017-01-06 | GSE93170 | 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.
2013-03-13 | GSE43878 | 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
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Project description:Analyzing serological differences between AMA positive and negative PBC using DIGE
2014-11-27 | PXD001152 | Pride
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are using RNA sequencing analysis to test the effects of overexpressing caspase-8 mutants or wild-type caspase-8 on the mRNA of KYSE150 cells. Methods: KYSE150 cells were transfected with caspase-8 mutants or wild-type caspase-8 for 48 hours in 1640 medium plus 10% serum. Two independent replicates were plated, transfected in parallel for each caspase-8 mutants or wild-type caspase-8. Results: Log-fold changes of mRNAs between caspase-8 mutants and wild-type caspase-8 group were selected with a significance threshod of p<0.05. There are 3974 overlapping differentially expressed genes in the caspase-8 mutant cells compared to the wild-type caspase-8 cells. Conclusions: Our study determined the mRNA changes of caspase-8 mutant KYSE150 cells compared to the wild-type caspase-8 cells.
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Project description:41K whole genome oligo-microarrays (Agilent Technologies) were used to characterize age-dependent changes in gene expression in peripheral blood cells (PBC) obtained from up to 8 individual NOD mice at 6 different time points (10 days (n=8), and 4 weeks (n=3), 8 weeks (n=7), 12 weeks (n=8), 16 weeks (n=7), and 20 weeks of age (n=4)), compared to NOD.B10 tissue controls. "Milestone Genes" are genes whose expression was significantly changed (approximately 3 fold) as the result of splicing or changes in transcript level. Milestone Genes were identified among genes within type one diabetes (T1D) susceptibility regions (Idd). Milestone Genes showing uniform patterns of changes in expression at various time points were identified. Potential T1D candidate genes were identified among Milestone Genes within Idd regions and/or hierarchical clusters. These studies identified tissue- and age-specific changes in gene expression that may play an important role in the inductive or destructive events of T1D. NOD/LtJ (NOD), NOD.B10Sn-H2b/J (NOD.B10) female mice of multiple ages were used for this study. Six Groups of NOD mice were sacrificed at 10 days, and 4, 8, 12, 16, and 20 weeks of age and peripheral blood cells (PBC) were removed and prepared for mRNA analysis. Two Groups of 10 NOD.B10 mice [10 days (n=10) + 20 weeks of age (n=10)] were used as a tissue specific control. Gene (mRNA) expression was analyzed using the 41K Whole Mouse Genome Oligo Microarray Kit (Agilent Technologies), and gene expression data are processed (cy3: NOD, cy5: NOD.B10) and reported as normalized expression ratios: Log 10 (NOD processed signal / NOD.B10 processed signal) (Log ratio). 10days of age; PBC_10d (n=8), 4 weeks of age; PBC_4w (n=3), 8 weeks of age; PBC_8w (n=7), 12 weeks of age; PBC_12w (n=8), 16 weeks of age; PBC_16w (n=7), 20 weeks of age; PBC_20w (n=4)
2010-06-09 | E-GEOD-21897 | biostudies-arrayexpress