Sustained ER Ca2+ Depletion Suppresses Protein Synthesis and Induces Activation-enhanced Cell Death in Mast Cells

Soboloff, Jonathan; Berger, Stuart A.

doi:10.1074/jbc.m112129200

Cited by 84 publications

(59 citation statements)

References 34 publications

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“…As shown in Fig. 8B, and as previously observed in murine mast cells (11), HL-60 cells challenged with these reagents exhibited increased phosphorylation of EIF2␣. In contrast, challenged E2R2 cells displayed significantly reduced EIF2␣ levels compared with WT, in accordance with their ability to sustain protein synthesis in the presence of Ec and Tg.…”

Section: E2r2 Cells Display Increased Resistance To Protein Synthesissupporting

confidence: 67%

“…Econazole (Ec) is an antifungal imidazole that depletes Ca 2ϩ from the ER of mammalian cells and blocks Ca 2ϩ influx (16,17). These effects result in sustained depletion of Ca 2ϩ from ER stores and profound inhibition of protein synthesis leading to cell death (11). We have shown that some transformed cells exhibit several orders of magnitude greater sensitivity to Ec than normal cells (12,13).…”

mentioning

confidence: 90%

“…We have shown that some transformed cells exhibit several orders of magnitude greater sensitivity to Ec than normal cells (12,13). This enhanced sensitivity may be due to the activated nature of tumor cells since we have shown that concurrent stimulation of cells with growth factors such as steel factor (9,11), epidermal growth factor, or bombesin (13) enhances cell death; this is a process we refer to as activation-enhanced cell death. However, the nature of the differential sensitivity is not fully understood.…”

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confidence: 98%

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Increased Calcium Influx and Ribosomal Content Correlate with Resistance to Endoplasmic Reticulum Stress-induced Cell Death in Mutant Leukemia Cell Lines

Zhang

Berger²

2004

Journal of Biological Chemistry

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Cell clones were derived by treatment of HL-60 cells with stepwise increasing concentrations of econazole (Ec), an imidazole antifungal that blocks Ca 2؉ influx and induces endoplasmic reticulum (ER) stress-related cell death in multiple mammalian cell types. Clones exhibit 20-to more than 300-fold greater resistance to Ec. Unexpectedly, they also display stable cross-resistance to tunicamycin, thapsigargin, dithiothreitol, and cycloheximide but not doxorubicin, etoposide, or Fas ligand. Phenotypic analysis indicates that the cells display increased store-operated calcium influx and resistance to ER Ca 2؉ store depletion by Ec. E2R2, the most resistant clone, was observed to maintain protein synthesis levels after treatment with Ec or thapsigargin. Expression of GRP78, an ER-based chaperone, was induced by these ER stress treatments but to equal degrees in HL-60 and E2R2 cells. By using microarray analysis, at least 15 ribosomal protein genes were found to be overexpressed in E2R2 compared with HL-60 cells. We also found that ribosomal protein content was increased by 30% in E2R2 as well as other clones. The resistance phenotype was partially reversed by the ribosome-inactivating protein saporin. Therefore, increased store-operated calcium influx, resistance to ER Ca 2؉ store depletion, and overexpression of ribosomal proteins define a novel phenotype of ER stress-associated multidrug resistance.Calcium signals play a central role in many cellular activities including cell movement, secretion, proliferation, gene transcription, and cell death (1, 2). In non-excitable cells, the endoplasmic reticulum (ER) 1 plays a key role in calcium signaling. Receptor-mediated activation of phospholipase C generates the second messenger inositol 1,4,5-triphosphate that diffuses rapidly through the cytosol to interact with inositol 1,4,5-triphosphate receptor on the ER membrane releasing calcium stored in the ER lumen. The resulting depletion of calcium within the ER triggers calcium entry from the extracellular milieu through the plasma membrane. This capacitive or store-operated calcium (SOC) influx (3) serves to both expand the initial calcium signal and replenish the emptied ER store (4, 5). Although the nature of SOC channel remains unclear, the importance of SOC influx in maintaining cell viability has been demonstrated in different studies (6 -13).In addition to its key role in Ca 2ϩ signaling, the ER is a site for protein synthesis, and these two functions intersect under conditions of ER stress. For instance, treatment of cells with thapsigargin (Tg), the inhibitor of the sarcoplasmic/endoplasmic Ca 2ϩ -ATPase responsible for transporting Ca 2ϩ into the ER, rapidly depletes ER Ca 2ϩ stores (14), inhibits the function of Ca 2ϩ -dependent chaperones, and triggers the unfolded protein response (15). Econazole (Ec) is an antifungal imidazole that depletes Ca 2ϩ from the ER of mammalian cells and blocks Ca 2ϩ influx (16, 17). These effects result in sustained depletion of Ca 2ϩ from ER stores and profound inhibition of prot...

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Section: E2r2 Cells Display Increased Resistance To Protein Synthesissupporting

confidence: 67%

mentioning

confidence: 90%

mentioning

confidence: 98%

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Increased Calcium Influx and Ribosomal Content Correlate with Resistance to Endoplasmic Reticulum Stress-induced Cell Death in Mutant Leukemia Cell Lines

Zhang

Berger²

2004

Journal of Biological Chemistry

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“…Studies in other cell systems showed that TG toxicity results primarily from mitochondrial Ca 2ϩ overload and secondarily from ER stress associated with Ca 2ϩ store depletion (45). Expression of hUCP4 blocked mitochondrial ROS formation by reducing the initial hyperpolarization and the subsequent depolarization of the inner mitochondrial membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Uncoupling Protein-4 Regulates Calcium Homeostasis and Sensitivity to Store Depletion-induced Apoptosis in Neural Cells

Chan

Liu

Kyriazis

et al. 2006

Journal of Biological Chemistry

104

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An increase in the cytoplasmic-free Ca2؉ concentration mediates cellular responses to environmental signals that influence a range of processes, including gene expression, motility, secretion of hormones and neurotransmitters, changes in energy metabolism, and apoptosis. Mitochondria play important roles in cellular Ca 2؉ homeostasis and signaling, but the roles of specific mitochondrial proteins in these processes are unknown. Uncoupling proteins (UCPs) are a family of proteins located in the inner mitochondrial membrane that can dissociate oxidative phosphorylation from respiration, thereby promoting heat production and decreasing oxyradical production. Here we show that UCP4, a neuronal UCP, influences store-operated Ca

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“…[7][8][9][10] Rises in both cytosolic and mitochondrial calcium have been reported in several cell types to lead to apoptosis. [11][12][13][14][15] BCR-ABL expression has been reported to modulate calcium homeostasis in the ER, and interfere with ER-mediated apoptotic pathways to promote survival of CML cells. 16 Changes in either the prevailing ER calcium levels and/or resultant calcium influx into the ER (known as capacitative calcium entry (CCE)) may compromise calcium-dependent apoptotic mechanisms in BCR-ABL-expressing cells.…”

Section: Introductionmentioning

confidence: 99%

Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis

2011

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Imatinib is a substrate for hOCT1 (SLC22A1) and inhibitors of this influx transporter, such as amantadine and prazosin, have previously been shown to decrease cellular imatinib uptake. However, here we report that in longer term experiments, both drugs paradoxically increase the cytotoxicity of all three currently licensed tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib. This effect is due to release of intracellular calcium from the endoplasmic reticulum (ER), with changes in mitochondrial calcium and alterations in mitochondrial membrane permeability, resulting in caspase-mediated apoptosis. The effect is confined to BCR-ABL-positive cells, and is greater in primary cells than in cell lines. Furthermore, in primary cells at original diagnosis, the effect is only seen in samples from patients destined to become complete cytogenetic responders to imatinib. These results indicate that calcium release from the ER, here induced by amantadine or prazosin, may prime BCR-ABL-positive cells to TKI-induced apoptosis. Amantadine/prazosin primed TKI cytotoxicity in vitro may be a useful test for the level of ER-releasable calcium, and may be of prognostic value.

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Sustained ER Ca2+ Depletion Suppresses Protein Synthesis and Induces Activation-enhanced Cell Death in Mast Cells

Abstract: Depletion of

Cited by 84 publications

References 34 publications

Increased Calcium Influx and Ribosomal Content Correlate with Resistance to Endoplasmic Reticulum Stress-induced Cell Death in Mutant Leukemia Cell Lines

Increased Calcium Influx and Ribosomal Content Correlate with Resistance to Endoplasmic Reticulum Stress-induced Cell Death in Mutant Leukemia Cell Lines

Mitochondrial Uncoupling Protein-4 Regulates Calcium Homeostasis and Sensitivity to Store Depletion-induced Apoptosis in Neural Cells

Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis

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