A Virus-acquired Host Cytokine Controls Systemic Aging by Antagonizing Apoptosis
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ABSTRACT:
PROVIDER: PRJNA436344 | ENA |
REPOSITORIES: ENA
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2018-07-02 | GSE111248 | GEO
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Project description:Human nephronophthisis and related ciliopathies suggest a link between ciliary signaling defects and altered DNA damage responses. The goal of our study is to elucidate the molecular link of both signaling systems as well as the role of altered DNA damage responses in kidney degeneration and fibrosis. The kinase-regulated DNA damage response target Apoptosis Antagonizing Transcription Factor (Aatf) is a master regulator of the p53 response. Upon genetic deletion of Aatf in renal tubular cells we induce progressive renal failure and a phenotype closely resembling human nephronophthisis in mice and are able to show Aatf as a regulator of primary cilia and modulator of the DNA damage response connecting two pathogenetic concepts of nephronophthisis and nephronophthisis-related ciliopathies. The analysis of the RNA-sequencing of four Aatf-knockout mice and four wildtype mice supports the experimental findings.
2019-03-31 | E-MTAB-7077 | biostudies-arrayexpress
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2016-06-15 | E-GEOD-38743 | biostudies-arrayexpress
Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other “death receptor” ligands may explain not only the inability of TRAIL and TRAIL “death receptor” agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell – mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). We showed that acquired TRAIL resistance was associated with complex disruption of both extrinsic and intrinsic apoptotic pathways manifested by acquired multi-drug resistant phenotype of TR1, TR2, and TR3 clones. To identify changes associated with TRAIL resistance of Jurkat cells we performed genome-wide gene expression analysis of TRAIL-resistant clones (TR) and compared to WT Jurkat cells. We identified significantly increased expression (1.33-fold change with adjusted p < 0.05) of 73 genes in TR1 clone, 53 genes in TR2 clone and 8 genes in TR3 clone, and significant decrease in expression (0.75-fold change with adjusted p < 0.05) of 174 genes in TR1 clone, 36 genes in TR2 clone and 28 genes in TR3 clone. There was an overlap of only 2 significantly overexpressed (midkine / MDK and zinc finger and BTB domain containing 16 gene / ZBTB16 / PLZF) and 4 downregulated genes (YAP1, IGJ, EIF1AY, RPS4Y1) in all three TR clones.
2016-06-15 | GSE38743 | GEO
Project description:In type 1 diabetes (T1D), the pancreatic β-cells are specifically destroyed by the immune system. In this process, local release of pro-inflammatory cytokines, such as IL-1β and IFNγ, contribute to β-cell apoptosis. Genome-wide association studies have identified more than 60 risk loci for T1D, including chr15q25.1 with the candidate gene CTSH (cathepsin H). We previously showed that T1D-associated risk variants in CTSH affect the expression of CTSH and are associated with disease progression in children with newly diagnosed T1D.We further found that CTSH increases β-cell function and protects against cytokine-induced apoptosis. Using global gene expression analysis, the purpose of the present study was to identify the genes and mechanisms through which CTSH mediates its protective effects. Microarray analysis identified a total of 63 annotated genes differentially expressed between stable CTSH-overexpressing insulin-secreting INS-1 cells and control cells transfected with an empty vector after treatment with IL-1β and IFNγ for 0, 6 and 16 hours. Permutation test taking all time-points into consideration identified 10 genes differentially expressed between the CTSH-overexpressing cells and the control cells: Elmod1, Fam49a, Gas7, Gna15, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified one significant pathway “Inflammation mediated by chemokine and cytokine signaling pathway” with the genes Gna15, Ptgs1 and Rac2. Since Gna15 and Rac2 were upregulated by CTSH overexpression, their expression was knocked down using small interfering RNAs (siRNAs) to evaluate their potential as mediators of the protective effect of CTSH. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis.
2020-09-01 | GSE136643 | GEO
Project description:The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics comparison of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor- and cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT and MAPK/ERK pathways, were activated in the radioresistant cells, leading to enhanced cell migration, invasion and epithelial-mesenchymal transition (EMT), and inhibition of apoptosis. We focused functional analysis on one of the most upregulated proteins in the radioresistant cells, CD73, which is a cell surface protein that is overexpressed in a variety types of cancer. Ectopic overexpression of CD73 in the parent cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 resensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies suggest that CD73 confers acquired radioresistance in pancreatic cancer cells at least in part through inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136. Furthermore, we found that knockdown of CD73 in the radioresistant cells alone reverted the gene expression and phenotype of the radioresistant cells from those of mesenchymal-like cells to the ones of epithelial cells, demonstrating that CD73 upregulation is required for maintaining EMT in the radioresistant cells. Our results support the notion that the enhanced growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity, and acquisition of cancer stem-like cell properties contributes to acquired radioresistance in the residual surviving cells after fractionated irradiation, and that CD73 is a novel downstream factor of those enhanced signaling and acts to confers acquired radioresistance and maintains EMT in the radioresistant pancreatic cancer cells.
2019-12-31 | PXD012922 | Pride
Project description:The Rac2 GTPase contributes to Cathepsin H-mediated protection against cytokine-induced β-cell apoptosis
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