Intracellular Staphylococcus aureus perturbs the host cell Ca2+-homeostasis to promote cell death
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ABSTRACT:
PROVIDER: PRJNA656694 | ENA |
REPOSITORIES: ENA
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Project description:The pathogen Staphylococcus aureus can invade and survive within human cells. There, the intracellular bacterium induces host cell death, which may facilitate spread of infection and tissue destruction. We here conducted a shRNA screen and infected the library of knock-down cells with S. aureus. We identified calcium signaling pathways to play a role in S. aureus invasion and cytotoxicity. For latter, the intracellular bacteria induce a cytoplasmic and mitochondrial Ca2+-overload, which results in host cell death.
2021-10-31 | GSE156073 | GEO
Project description:Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning results in the distension of the alveolar structures by the accumulation of milk, which, in turn, activates STAT3 and initiates a caspase-independent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary involution is well established, it has not been entirely clear how milk stasis activates STAT3. In this report, we demonstrate that protein levels of the PMCA2 calcium pump are significantly downregulated within 2-4 hours of experimental milk stasis. Reductions in PMCA2 expression correlate with an increase in cytoplasmic calcium in vivo as measured by multiphoton intravital imaging of GcAMP6f fluorescence. These events occur concomitant with the appearance of nuclear pSTAT3 expression and prior to significant activation of LIF, IL6 and TGFb3 production or LDCD. Interestingly, we observed the activation of TFEB led by activation of TGFb signaling and deactivation of mTOR signaling in the involution of mammary gland. Finally, we demonstrate that increased intracellular calcium activates STAT3 by degrading SOCS3 mediated by TGFb signaling. In summary, these data suggest that intracellular calcium serves as an important biochemical signal linking milk stasis to STAT3 activation, increased lysosome biogenesis, and lysosome-mediated cell death.
2022-12-01 | GSE190031 | GEO
Project description:About 20-30% of patients with metastatic non-medullary thyroid cancer (TC) have persistent or recurrent disease resulting from tumor dedifferentiation. Tumor redifferentiation to restore sensitivity to radioactive iodine therapy is considered a promising strategy to overcome RAI resistance. Autophagy has emerged as an important mechanism in cancer dedifferentiation. Here, we demonstrate the therapeutic potential of autophagy activation for redifferentiation in thyroid cancer cell lines. Five, all digitalis-like compounds, restored hNIS expression and iodine uptake in TC cell lines. Upregulation of hNIS was mediated by intracellular Ca2+ and cFOS activation. Cell proliferation was inhibited by downregulating Akt1 and by induction of autophagy and p21-dependent cell cycle arrest. All together, digitalis-like compounds could represent a promising treatment modality for patients with dedifferentiated TC.
2016-11-14 | GSE79400 | GEO
Project description:Staphylococcus lentus Ca2 genome sequence
| PRJEB278 | ENA
Project description:Altered Ca2+ handling has both immediate physiological effects and long-term genomic effects on vascular smooth muscle function. Previously we have shown that elevation of cytoplasmic Ca2+ through voltage-dependent Ca2+ channels (VDCCs) or store-operated Ca2+ channels (SOCCs) results in phosphorylation of the Ca2+/cAMP response element binding protein (CREB) in cerebral arteries. Here we demonstrate that stimulation of these different Ca2+ influx pathways results in transcriptional activation of a distinct, yet overlapping set of genes, and that the induction of selected CRE-regulated genes is prevented by the addition of corresponding Ca2+ channel blockers. Using oligonucleotide array analysis, changes in mRNA levels were quantified following membrane depolarization with K+ or depletion of intracellular Ca2+ stores with thapsigargin in human cerebral vascular smooth muscle cells. Array results for differentially regulated genes containing a CRE were confirmed by quantitative RT-PCR, and corresponding changes in protein expression were shown by Western blot analysis and immunofluorescence. Membrane depolarization induced a transient increase in c-fos mRNA and a sustained increase in early growth response-1 (Egr-1) mRNA and protein that were inhibited by application of the VDCC blocker, nimodipine, and the SOCC inhibitor, 2-aminoethoxydiphenylborate (2-APB). Thapsigargin induced a sustained increase in c-fos mRNA and MAP kinase phosphatase-1 (MKP-1) mRNA and protein, and these effects were decreased by 2-APB but not by nimodipine. Our findings thus indicate that Ca2+ entry through VDCCs and SOCCs can differentially regulate CRE-containing genes in vascular smooth muscle and imply that signals involved in growth modulation are both temporally and spatially regulated by Ca2+. Keywords: stress response
2006-03-16 | GSE2883 | GEO
Project description:Objective: To examine the role of carbonic anhydrase II (CA2 gene), the most efficient isoform in the CA family of zinc-containing metalloenzymes, in chondrocyte metabolism. Methods: CA2 expression was measured in human and mouse osteoarthritic cartilage. RNA-seq was performed in C28/I2 cells in which CA2 was silenced. Normal human chondrocytes were cultured under normoxia (21% oxygen) or hypoxia (2% oxygen) following CA2 knockdown. Cell metabolism was studied by measuring extracellular lactate production, glucose consumption, intracellular ADP/ATP, intracellular pH, and ROS production. Glycolysis was measured using Seahorse XF96 analyzer. The effect of CA2 knockdown on anabolic and catabolic markers was measured following treatment with IL-1. Effects of CA2 was examined on cell proliferation, cell-cycle distribution, colony-formation, and migration. Results: CA2 was highly elevated in human and murine osteoarthritic cartilage. RNA-seq analysis revealed that processes related to glycolysis, apoptosis and TNF signaling were perturbed in cells lacking CA2. CA2 expression was 10-fold higher under hypoxia and its knockdown caused decreased extracellular lactate production, increased ADP/ATP ratio, impaired glycolysis, decreased glycolytic capacity and lowered the expression of glycolysis rate-limiting enzymes, but did not affect intracellular pH and ROS production. CA2 deficiency disturbed chondrocyte anabolic and catabolic equilibrium. CA2 knockdown suppressed chondrocyte migration and proliferation and induced cell-cycle arrest. Conclusion: This study unravels a novel role of CA2 in chondrocyte metabolism and inflammation. These findings indicate that CA2 is required for the maintenance of chondrocyte metabolic homeostasis. Future work is needed to further illuminate the mechanistic and functional role of CA2 in osteoarthritis development.
2022-03-17 | GSE184062 | GEO
Project description:The goals of this study are to determine effects of mitochondrial Ca2+ homeostasis on inter-compartmental proteostasis
2021-10-18 | PXD029171 | iProX
Project description:Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.
| EGAS00001005448 | EGA
Project description:The nephrotoxic ifosfamide-metabolite chloroacetaldehyde (CAA) induces changes in intracellular Ca2+-concentration of human RPTEC. This effect is due to a PKA-dependent inhibition of Na+/Ca2+ exchange (Benesic, A., Schwerdt, G. at. al. (2005) Kidney Int 68, 2029-2041). Thus, possible effects of CAA-exposure on cAMP and Ca2+ regulated genes as well the Ca2+/NFAT pathway were investigated by cDNA-microarray analysis. Both microarrays (cAMP/Ca2+ and Ca2+(NFAT) were performed twice. After 24 h CAA exposure a marked downregulation of c-fos and junB was observed in all arrays performed. In the cAMP/Ca2+-arrays downregulation of FOS, ADRB1, INHBA, CDK5, IL2, PLN, SRF, GCG, SGK, JUNB, BDNF, S100A6, CCNA1, MIF, HK2, SST and EGR2 by CAA was observed in two independent experiments. From the AP-1 family expression of junD and fosB were not altered. Overexpression by CAA of CREB and DDIT3 were only observed in one of two experiments. JUND, FOSB, FOSL1, CREM and CREBBP expression was not influenced in reproducible manner, as well as all members of the NFAT-family. In the Ca2+/NFAT-Arrays, PPP3CB, VAV3, NFATC1, IL8, IL6, FASLG, IL3, IFNB1, FOS, BCL2, EGR3, CD3G, HRAS, EP300, IL4, CALM3, RELA, EGR2, NPPB, IFNG, NFATC4, KPNA5, CAMK2BNFKB2 , VEGF, IL8RA, IL2,GATA4, MEF2A, PTPRC, ICOS, NFKBIE, CDKN1A, CSNK2B, ACTB, MEF2B and JUNB mRNA´s were repeatedly reduced by CAA exposure. The only gene with upregulation in both experiments was found to be IFN-alpha. Thus CAA exposure for 24 h leads to a downregulation of of the AP-1 members JUNB and FOS, whereas there is small positive effect on CREB mRNA. CAA reproducibly lowers the expression of IL-2, 3, 4, 6 and 8, whereas the levels of TNFalpha and TGFbeta1 and 3 mRNA were not altered. IFN-alpha mRNA levels were reproducibly increased (>2-fold). In conclusion, CAA seems to interact with Ca2+ and cAMP signalling pathways, with a strong impact on AP-1 proteins and inflammatory signalling. Keywords: stress response to toxic agent
2006-06-30 | GSE4956 | GEO
Project description:The investigators hypothesize that Ca2+/MG2+ infusions will not have a significant effect on oxaliplatin pharmacokinetics.
| 2091675 | ecrin-mdr-crc