Life and Death of Lymphocytes: A Volume Regulation Affair

Bortner, Carl D.; Cidlowski, John A.

doi:10.1159/000335864

Cited by 20 publications

(19 citation statements)

References 55 publications

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“…(c) Jurkat cells were treated with diluent or 10 ng/ml TRAIL for 4.5 h, stained with annexin V-APC and 1 mg/ml lysotracker green, and analyzed by flow cytometry decrease in surface area, resulting in excess plasma membrane, we postulated that cytoplasmic vesicle formation might result from cell shrinkage, another widely observed feature of apoptosis. 23,24 To assess this possibility, we induced cell shrinkage by acute exposure to mannitol. 25 Extensive intracellular vesicle formation similar to that seen in apoptotic cells was observed in mannitol-treated cells (Figures 6a-d and f), raising the possibility that cytoplasmic vesicle formation reflects internalization of plasma membrane through mechanical processes when cells shrink during apoptosis or in response to osmotic stimuli.…”

Section: Resultsmentioning

confidence: 99%

Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm

et al. 2012

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Phosphatidylserine (PS) exposure on the external leaflet of the plasma membrane is widely observed during apoptosis and forms the basis for the annexin V binding assay to detect apoptotic cell death. Current efforts to explain PS exposure focus on two potential mechanisms, activation of a phospholipid scramblase or calcium-mediated trafficking of lysosomes to the cell surface. Here, we provide evidence that apoptotic PS exposure instead reflects bidirectional trafficking of membrane between the cell surface and cytoplasm. Using a series of cell lines, some of which expose large amounts of PS during apoptosis and some of which do not, we demonstrate that accumulation of plasma membrane-derived cytoplasmic vesicles in a dynamin-, clathrin-and Cdc42-independent manner is a previously undescribed but widely occurring feature of apoptosis. The apoptotic exposure of PS occurs when these vesicles traffic back to cell surface in a calcium-dependent process that is deficient in a substantial fraction of human cancer cell lines. These observations provide a new model for PS externalization during apoptosis and simultaneously identify an altered step that accounts for the paucity of apoptotic PS exposure in many cell lines. Cell Death and Differentiation (2013) 20, 64-76; doi:10.1038/cdd.2012; published online 3 August 2012A common feature of apoptosis from Caenorhabditis elegans to man is the transfer of phosphatidylserine (PS) and phosphatidylethanolamine, which ordinarily reside on the cytoplasmic surface of the membranes, to the cell surface.

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Section: Resultsmentioning

confidence: 99%

Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm

et al. 2012

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“…One hallmark of apoptosis is the loss of cell volume or cell shrinkage [36][37][38], termed apoptotic volume decrease (AVD) [39]. The loss of cell volume or AVD during apoptosis has been shown to result from changes in intracellular ions, with the loss of intracellular potassium playing a critical role in the downstream activation of the apoptotic machinery [34,35,40,41].…”

Section: Ions and Apoptosismentioning

confidence: 99%

Ion channels and apoptosis in cancer

Bortner

Cidlowski

2014

Phil. Trans. R. Soc. B

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111

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Humans maintain a constant cell number throughout their lifespan. This equilibrium of cell number is accomplished when cell proliferation and cell death are kept balanced, achieving a steady-state cell number. Abnormalities in cell growth or cell death can lead to an overabundance of cells known as neoplasm or tumours. While the perception of cancer is often that of an uncontrollable rate of cell growth or increased proliferation, a decrease in cell death can also lead to tumour formation. Most cells when detached from their normal tissue die. However, cancer cells evade cell death, tipping the balance to an overabundance of cell number. Therefore, overcoming this resistance to cell death is a decisive factor in the treatment of cancer. Ion channels play a critical role in cancer in regards to cell proliferation, malignant angiogenesis, migration and metastasis. Additionally, ion channels are also known to be critical components of apoptosis. In this review, we discuss the modes of cell death focusing on the ability of cancer cells to evade apoptosis. Specifically, we focus on the role ion channels play in controlling and regulating life/death decisions and how they can be used to overcome resistance to apoptosis in the treatment of cancer.

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“…[Ca 2+ ] i plays a pivotal role in the regulation of lymphocyte function [14] and survival [15,16,17]. During T lymphocyte activation, TCR stimulation is followed by phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate with generation of inositol-1,4,5-trisphosphate (IP3) and polyunsaturated diacylglycerol (DAG) [14].…”

Section: Introductionmentioning

confidence: 99%

AMPKα1-Sensitivity of Orai1 and Ca<sup>2+</sup> Entry in T - Lymphocytes

Bhavsar

Schmidt²,

Bobbala³

et al. 2013

Cell Physiol Biochem

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Background/Aims: T-lymphocyte activation and function critically depends on Ca²⁺ signaling, which is regulated by store operated Ca²⁺ entry (SOCE). Human and mouse T lymphocytes express AMP activated kinase AMPKα1, which is rapidly activated following elevation of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) by treatment of the cells with Ca²⁺ ionophore or following inhibition of endosomal Ca²⁺ ATPase with thapsigargin. AMPK is further activated by triggering of the T cell antigen receptor (TCR). The present study explored whether AMPK influences Ca²⁺ entry and Ca²⁺-sensitive regulation of T-lymphocyte function. Methods: T-lymphocytes were isolated and cultured from AMPKα1-deficient (ampk^-/-) mice and from their wildtype (ampk^+/+) littermates. The phenotype of the cells was analysed by flow cytometry, [Ca²⁺]_i estimated from Fura-2 fluorescence, SOCE from increase of [Ca²⁺]_i following thapsigargin treatment (1 µM), and cell function analysed by measuring cytokine secretion and western blotting. Results: Expression of surface markers in CD4⁺ and CD8⁺ T-cells were similar in ampk^-/- and ampk^+/+ T-lymphocyte blasts. Moreover, total STIM1 protein abundance was similar in ampk^-/- and ampk^+/+ T-lymphocyte blasts. However, Orai1 cell membrane protein abundance was significantly higher in ampk^-/- than in ampk^+/+ T-lymphocyte blasts. SOCE and increase of [Ca²⁺]_i following TCR activation by triggering TCR with anti-CD3 and cross-linking secondary antibody were both significantly more pronounced in ampk^-/- than in ampk^+/+ T-lymphocyte blasts. The difference of Ca²⁺ entry between ampk^-/- and ampk^+/+ T-lymphocytes was abrogated by Orai1 inhibitor 2-aminoethoxydiphenyl borate (2-APB, 50 µM). Proliferation of unstimulated ampk^-/- lymphocytes was higher than proliferation of ampk^+/+ T-lymphocytes, a difference reversed by Orai1 silencing. Conclusions: AMPK downregulates Orai1 and thus SOCE in T-lymphocytes and thus participates in negative feed-back regulation of cytosolic Ca²⁺ activity.

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Life and Death of Lymphocytes: A Volume Regulation Affair

Cited by 20 publications

References 55 publications

Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm

Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm

Ion channels and apoptosis in cancer

AMPKα1-Sensitivity of Orai1 and Ca<sup>2+</sup> Entry in T - Lymphocytes

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