Gene expression alterations in transporters with Pb (lead) exposure in mice tissues
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE93544 | GEO | 2017/07/12
SECONDARY ACCESSION(S): PRJNA361080
REPOSITORIES: GEO
Similar Datasets
Project description:Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store-operated Ca2+ entry (SOCE) triggering activation of transcription factors. Here, we characterize Stim1A, a splice variant with an additional 31 amino acid domain inserted in frame within its cytosolic domain. Prominent expression of exon A is found in astrocytes, heart, kidney and testes. Full length Stim1A functions as a dominant-negative regulator of SOCE and ICRAC, facilitating sequence specific fast calcium dependent inactivation and destabilizing gating or Orai1. Downregulation or absence of native Stim1A results in increased SOCE. Despite reducing SOCE, Stim1A leads to increased NFAT translocation. Differential proteomics revealed interference of Stim1A with the cAMP-SOCE crosstalk by altered modulation of phosphodiesterase (PDE8B), resulting in reduced cAMP degradation and increased PIP5K activity, facilitating an increased NFAT activation. Our study uncovers a hitherto unknown mechanism regulating NFAT activation and indicates that cell type specific splicing of Stim1 is a potent means to regulate the NFAT signalosome and cAMP-SOCE crosstalk.
2021-11-11 | PXD028974 | Pride
Project description:Magnesium is essential for cellular life, but how it is homeostatically controlled still remains poorly understood. Here we report that members of CNNM family, which have been controversially implicated in both cellular Mg2+ influx and efflux, selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Co-expression of CNNMs with the channel markedly increased uptake of divalent cations, which is prevented by an inactivating mutation to the channel’s pore. Knockout of Trpm7 in cells or application of the TRPM7-channel inhibitor NS8593 also interfered with CNNM-stimulated divalent cation uptake. Conversely, knockout of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry, without affecting TRPM7 protein expression or its cell surface levels. Furthermore, we found that cellular overexpression of Phosphatases of Regenerating Liver (PRLs), a known CNNMs binding partner, stimulated TRPM7-dependent divalent cation entry and that CNNMs were required for this activity. Whole-cell electrophysiological recordings demonstrated that deletion of CNNM3 and CNNM4 from HEK-293 cells interfered with heterologously expressed and native TRPM7 channel function. We conclude that CNNMs employ the TRPM7 channel to mediate divalent cation influx and that CNNMs also possess separate TRPM7-independent Mg2+ efflux activities that contribute to CNNMs’ control of cellular Mg2+ homeostasis.
2021-11-15 | PXD026635 | Pride
Project description:STIM1 is a Ca2+ sensor of intracellular Ca2+ stores and essentially activates the Ca2+ entry channels of the plasma membrane. STIM1 is predicted to activate transient receptor potential canonical (TRPC) channels and Orai channels, and has a critical role in promoting the development of cardiac hypertrophy. Gene array experiments were performed to analyze the effects of STIM1 deficiency using total RNA from the left ventricles of WT sham, WT TAC, STIM1KO sham and STIM1KO TAC 4 weeks after the operation.
2014-07-01 | E-GEOD-38733 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of T cell progenitors that in most patients is associated with activating mutations in the NOTCH1 pathway. Recent reports have indicated a link between Ca2+ homeostasis in the endoplasmic reticulum (ER), the regulation of NOTCH1 signaling and T-ALL. Here we investigated the role of store-operated Ca2+ entry (SOCE) in T-ALL. SOCE is a Ca2+ influx pathway that is mediated by the plasma membrane Ca2+ channel ORAI1 and its activators STIM1 and STIM2. Deletion of STIM1 and STIM2 in leukemic cells abolished SOCE and significantly prolonged the survival of mice in a NOTCH1-driven model of T-ALL. The survival advantage was unrelated to leukemia development and leukemic cell burden, but was associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with wildtype T-ALL showed a severe necroinflammatory response in their bone marrow, which was absent in mice with Stim1/2-/- leukemia. Several signaling pathways previously linked to cancer-induced inflammation were downregulated in Stim1/2-/- leukemic cells, likely accounting for less aggressive leukemia progression and prolonged survival of mice. Our study shows that T-ALL is associated with inflammation of leukemia-infiltrated organs and that SOCE controls the proinflammatory effects of leukemic T lymphoblasts.
2018-07-11 | GSE116776 | GEO
Project description:Immunity to fungal infections is mediated by cells of the innate and adaptive immune system. Activation of immune cells requires Ca2+ influx through the Ca2+ channel ORAI1, which is activated by stromal interaction molecule 1 (STIM1). Th17 cells are essential for immunity to C. albicans infection and require Ca2+ influx for expression of IL-17A and other Th17 cytokines. In mice, deletion of STIM1 and thus Ca2+ influx in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell-specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion in CD4 T cells had different effects on gene expression programs in pathogenic (proinflammatory) and non-pathogenic Th17 cells. STIM1 deletion in non-pathogenic Th17 cells, which are required for antifungal immunity, compromised the expression of genes in several metabolic pathways including Foxo and HIF-1a signaling as well as the TCA cycle and oxidative phosphorylation (OXPHOS). Consequently, STIM1 deficient non-pathogenic Th17 cells had impaired glycolysis and mitochondrial respiration. By contrast, STIM1 deletion in pathogenic Th17 cells showed only attenuated mitochondrial function but normal glycolysis.
2020-06-01 | GSE149162 | GEO
Project description:Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multi-systemic signs including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both regulating Ca2+ homeostasis through the ubiquitous SOCE (store-operated Ca2+ entry) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology, an increase of thrombocytes, and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA- sequencing detected more than 1200 dysregulated genes in Stim1R304W/+ mice and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multi-systemic TAM/STRMK signs, and we identified myostatin as a suitable biomarker for TAM/STRMK in human and mouse.
2024-03-13 | GSE244524 | 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:STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that serves to replenish ER Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai1 channels in a process known as store operated calcium entry (SOCE). Previously, we have shown that SOCE is impaired in the diabetic pancreatic β cell; however, the consequences of reduced β cell SOCE have not been well studied. To test this, we generated mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ). Our results revealed a striking sexual dimorphism in metabolic phenotypes when STIM1Δβ mice were challenged with high fat diet for 8 weeks. Male STIM1Δβ mice showed no differences in total weight, lean or fat mass, or glucose tolerance compared to WT littermate controls. In contrast, female STIM1Δβ mice displayed significantly increased total body weight, fat mass, and reduced glucose tolerance, in vivo glucose-stimulated insulin secretion and β cell mass compared to WT littermate controls, while insulin sensitivity, food intake, and energy expenditure were unchanged. To investigate mechanisms underlying these findings, RNA sequencing was performed in isolated islets and revealed altered 17-beta estradiol (E2) signaling, lipid metabolism, epithelial cell differentiation and decreased noncanonical estradiol receptor GPER. Consistent with this, alpha cell mass was increased in female STIM1Δβ, while proteomics and immunoblot analysis of STIM1 knockout (STIM1KO) INS-1 beta cells revealed reduce insulin expression and increased glucagon expression, suggesting STIM1 may be required for the maintenance of β cell identity. To this end, we show that a reduction of a noncanonical estradiol receptor GPER in STIM1 deficient islets contributes to the marked sexual dimorphism observed during beta cell dysfunction in female STIM1Δβ mice. This present study delineates a sexually dimorphic regulation of STIM1 in the maintenance of pancreatic beta cell identity through GPER and may expand the field of therapeutic approaches to diabetes. Our findings demonstrate the importance of STIM1 and GPER expression stability in the anti-diabetogenic response from estradiol.
2023-08-15 | GSE208135 | GEO
Project description:T Cell Receptor-Induced NF-kB Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-Mediated Calcium Entry
| PRJNA308743 | ENA
Project description:STIM1 is a Ca2+ sensor of intracellular Ca2+ stores and essentially activates the Ca2+ entry channels of the plasma membrane. STIM1 is predicted to activate transient receptor potential canonical (TRPC) channels and Orai channels, and has a critical role in promoting the development of cardiac hypertrophy.
2014-07-01 | GSE38733 | GEO