Store Independent Ca2+ Entry Regulates the DNA Damage Response Pathway in Breast Cancer Cells
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PROVIDER: PRJNA624914 | ENA |
REPOSITORIES: ENA
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Project description:The mainstay of treatment for hormone responsive breast tumors is chemotherapy, followed by targeted endocrine therapy. The vast majority (80%) of estrogen receptor positive tumors also express wild type p53 protein that is the main determinant of the DNA damage response. Tumors that are ER+ and p53WT respond poorly to chemotherapy, although the underlying mechanisms are not completely understood. We describe a novel link between store independent Ca2+ entry (SICE) and resistance to DNA damaging drugs, mediated by the secretory pathway Ca2+-ATPase, SPCA2. In luminal ER+/PR+ breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. Independent of ion pump activity, SPCA2 elevates baseline Ca2+ levels through SICE and drives cell proliferation. Attenuation of SPCA2 led to increased mitochondrial ROS production, DNA damage and activation of the ATM/ATR-p53 axis leading to G0/G1 phase cell cycle arrest and apoptosis. Resistance to DNA damaging agents including doxorubicin, carboplatin, and ionizing radiation could be reversed by downregulation of SPCA2 expression using curcumin. In conclusion, elevated SPCA2 drives pro-survival and chemotherapy resistance in ER+ p53WT breast tumors by suppressing the DNA damage response. Attenuation of SPCA2 expression by curcumin may have therapeutic potential in treating receptor positive breast cancer. The goal of this study is to investigate store Independent Ca2+ entry regulation of the DNA Damage Response pathway in breast cancer cells
2022-01-26 | GSE148537 | GEO
Project description:This series of microarray experiments monitored the gene expression profiles for monoclonal cell lines (derived from HEK-293 parental cell culture) with high (H1, H15, H24, H36, H39) or low (L3, L28, L29) levels of store-operated Ca2+ entry (SOCE). For selection of clones, HEK-293 cells were loaded with indo-1 and sorted by FACS on the basis of their cyclopiazonic acid (CPA)-stimulated Ca2+ entry. Monoclonal cell lines were selected from the sorted cells and their levels of SOCE confirmed by monitoring thapsigargin-stimulated Ba2+ entry. Total RNA was extracted from cells immediately after removal from their growth environment. RNA was processed and hybridized to the Affymetrix HG-U133A chip. Two parallel hybridizations were done for each RNA preparation from each monoclonal cell line or from the parental HEK-293 cell culture.
2007-08-03 | E-GEOD-1309 | biostudies-arrayexpress
Project description:T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity. RNAseq analyses of WT and Stim1Stim2 DKO follicular T cells and non-follicular T cells; 4-6 mice per cohort in duplicates. Mice were infected for 10 days with LCMV.
2016-03-10 | E-GEOD-79039 | biostudies-arrayexpress
Project description:This series of microarray experiments monitored the gene expression profiles for monoclonal cell lines (derived from HEK-293 parental cell culture) with high (H1, H15, H24, H36, H39) or low (L3, L28, L29) levels of store-operated Ca2+ entry (SOCE). For selection of clones, HEK-293 cells were loaded with indo-1 and sorted by FACS on the basis of their cyclopiazonic acid (CPA)-stimulated Ca2+ entry. Monoclonal cell lines were selected from the sorted cells and their levels of SOCE confirmed by monitoring thapsigargin-stimulated Ba2+ entry. Total RNA was extracted from cells immediately after removal from their growth environment. RNA was processed and hybridized to the Affymetrix HG-U133A chip. Two parallel hybridizations were done for each RNA preparation from each monoclonal cell line or from the parental HEK-293 cell culture. Keywords: parallel sample
2004-06-08 | GSE1309 | GEO
Project description:T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity.
2016-03-10 | GSE79039 | GEO
Project description:Abstarct:Mutations in the endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) result is a number of disease states including abnormal enamel formation. However, these defects in enamel have remained unclear given a lack of animal models available. We generated Stim1/2K14Cre mice to ablate the activity of STIM1 and its homologue STIM2 in enamel cells. These mice showed impaired Ca2+ entry in enamel cells and although enamel formed, it was severely hypomineralized and mechanically weak. RNA-sequencing of enamel cells provided a global overview of loss of Ca2+ sensor activity. ER stress markers associated with unfolded protein response (UPR) were increased. Cell morphology was altered showing loss of the typical ruffled-border and mislocalized mitochondria. We also identified decreased glutathione system and potentially associated with this, increased ROS and abnormal mitochondria. The Ca2+ extrusion system and enamel gene expression were also altered. These data might represent the first in vivo study linking Stim1/2 ablation with increased UPR function, decreased glutathione metabolism, increased ROS and abnormal mitochondria. Loss of ER Ca2+ sensors Stim1/2 in enamel cells has substantial detrimental effects at the cell and mineral phase level.
2017-01-17 | GSE93655 | GEO
Project description:Calcium is a critical signaling molecule in many cell types including immune cells. The calcium-release activated calcium channels (CRAC) responsible for store-operated calcium entry (SOCE) in immune cells are gated by STIM family members functioning as sensors of Ca2+ store content in the endoplasmic reticulum. We investigated the effect of SOCE blocker BTP2 on human peripheral blood mononuclear cells (PBMC) stimulated with the mitogen phytohemagglutinin (PHA).
2023-08-07 | GSE226570 | GEO
Project description:The purpose is to have a overview on how chronic dysfunction of store-operated calcium entry change transcription profiles of adult fly fat tissue. Methods:To achieve chronic dysfunction of store-operated calcium entry, we carried out the Temperature-caused RNAi Pulse Induction of Stim (29 celcius degree incubation, Stim-TRiPI, or Stim-TRIP in data file) in fat storage tissue of 6 days old adult male flies. At day 10 and 11 after Stim-TRiPI (Stim-TRIP), we isolated the fat tissues and carried out RNAseq analysis based gene-level read counts.
2019-05-07 | GSE112689 | GEO
Project description:Calcium signals are initiated in immune cells by the process of store-operated calcium entry (SOCE), where receptor activation triggers transient calcium release from the endoplasmic reticulum, followed by opening of plasma membrane calcium-release activated calcium (CRAC) channels. ORAI1, ORAI2 and ORAI3 are known to comprise the CRAC channel, however the contributions of individual isoforms to neutrophil function is not well understood. Here we show that loss of ORAI1 partially decreases calcium influx while loss of both ORAI1 and ORAI2 completely abolishes store-operated calcium entry. In other immune cell types, loss of ORAI2 enhances SOCE. In contrast, we find that ORAI2-deficient neutrophils display decreased calcium influx, which is correlated with measurable differences in regulation of neutrophil membrane potential via KCa3.1. Decreased SOCE in ORAI1-, ORAI2- and ORAI1/2-deficient neutrophils impairs multiple neutrophil functions including phagocytosis, degranulation, leukotriene and ROS production, rendering ORAI1/2-deficient mice highly susceptible to staphylococcal infection. This study demonstrates that ORAI1 and ORAI2 are the primary components of the neutrophil CRAC channel and identifies novel subpopulations of neutrophils where cell membrane potential functions as a rheostat to modulate the SOCE response. These findings have implications for new mechanisms that modulate neutrophil function during infection, acute and chronic inflammatory conditions, and cancer.
2020-09-01 | GSE157200 | GEO
Project description:Ca2+ release-activated Ca2+ entry is a potent host innate immune defence against influenza A virus
| PRJNA494313 | ENA