The role of calcium in the regulation of apoptosis

McConkey, David J.; Orrenius, Sten

doi:10.1002/jlb.59.6.775

Cited by 261 publications

(175 citation statements)

References 55 publications

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“…Calcium is thought to play a role in many model systems of apoptosis (26,27). For example, in thymocytes, an increase in intracellularcalciumisthoughttoactivateacalcium/magnesiumdependent endonuclease which leads to DNA fragmentation, and in many cells, elevation of intracellular calcium with the use of ionophores and/or thapsigargin can induce apoptosis (22,23,26,28).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…For example, in thymocytes, an increase in intracellularcalciumisthoughttoactivateacalcium/magnesiumdependent endonuclease which leads to DNA fragmentation, and in many cells, elevation of intracellular calcium with the use of ionophores and/or thapsigargin can induce apoptosis (22,23,26,28). Along these lines, the oncogene bcl-2 associated with inhibition of apoptosis, may act in part, by controlling extrusion of calcium from mitochondria and endoplasmic reticulum (26). Calcium-dependent intracellular targets relevant to the process of apoptosis likely include endonucleases (26), transglutaminases (29,30), and importantly, the proteolytic cascades involving calpain (31) and the caspases (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

“…Along these lines, the oncogene bcl-2 associated with inhibition of apoptosis, may act in part, by controlling extrusion of calcium from mitochondria and endoplasmic reticulum (26). Calcium-dependent intracellular targets relevant to the process of apoptosis likely include endonucleases (26), transglutaminases (29,30), and importantly, the proteolytic cascades involving calpain (31) and the caspases (32)(33)(34). Indeed, a recent report suggesting the appearance of outer leaflet PS requires caspase activation (32,35) led us to experiments employing various interleukin-1␤-converting enzyme (caspase) inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Bratton

Fadok

Richter

et al. 1997

Journal of Biological Chemistry

418

294

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Phosphatidylserine (PS), ordinarily sequestered in the plasma membrane inner leaflet, appears in the outer leaflet during apoptosis, where it triggers non-inflammatory phagocytic recognition of the apoptotic cell. The mechanism of PS appearance during apoptosis is not well understood but has been associated with loss of aminophospholipid translocase activity and nonspecific flip-flop of phospholipids of various classes. The human leukemic cell line HL-60, the T cell line Jurkat, and peripheral blood neutrophils, undergoing apoptosis induced either with UV irradiation or anti-Fas antibody, were probed in the cytofluorograph for (i) surface PS using fluorescein isothiocyanate-labeled annexin V, (ii) PS uptake by the aminophospholipid translocase using [6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino] caproyl] (NBD)-labeled PS, (iii) nonspecific uptake of phospholipids (as a measure of transbilayer flip-flop) using NBDlabeled phosphatidylcholine, and (iv) the appearance of hypodiploid DNA. In all three types of cells undergoing apoptosis, the appearance of PS followed loss of aminophospholipid translocase and was accompanied by nonspecific phospholipid flip-flop. Importantly, however, in the absence of extracellular calcium, the appearance of PS was completely inhibited despite DNA fragmentation and loss of aminophospholipid translocase activity, the latter demonstrating that loss of the translocase is insufficient for PS appearance during apoptosis. Furthermore, while both the appearance of PS and nonspecific phospholipid uptake demonstrated identical extracellular calcium requirements with an ED 50 of nearly 100 M, the magnitude of PS appearance depended on the level of aminophospholipid translocase activity. Taken together, the data strongly suggest that while nonspecific flip-flop is the driving event for PS appearance in the plasma membrane outer leaflet, aminophospholipid translocase activity ultimately modulates its appearance.The appearance of phosphatidylserine in the outer leaflet of the plasma membrane appears to be a universal phenomenon in cells undergoing apoptosis, or programmed cell death (1). Importantly, outer leaflet PS likely serves as a signal in tissues for the noninflammatory engulfment of apoptotic cells (Ref. 2 and see "Discussion"), a distinctly different response than the pro-inflammatory events following tissue necrosis. While phosphatidylserine (PS) 1 is actively transported from the outer to the inner leaflet by the aminophospholipid translocase (3-5), the mechanism(s) by which PS appears in apoptosis is not well understood. Verhoven et al. (3) reported that PS appearance was accompanied by both loss of aminophospholipid translocase activity and enhanced nonspecific transbilayer movement of phospholipids, perhaps due to activation of a "scramblase." Hence, they proposed that PS may become detectable in the outer leaflet due to the combination of these two events. However, to date, the relative contribution of these two events has not been clarified. Additionally, it is not known what role...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Bratton

Fadok

Richter

et al. 1997

Journal of Biological Chemistry

418

294

View full text Add to dashboard Cite

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“…In some of these injurious processes, disruption of cellular Ca# + homoeostasis, especially elevations of cytosolic Ca# + concentration, is considered to play a decisive intermediary role [4]. Accordingly, effects of Bcl-2 on Ca# + homoeostasis and on Ca# + -mediated cell death have been studied in a number of experimental models [5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Protection against hydrogen peroxide cytotoxicity in Rat-1 fibroblasts provided by the oncoprotein Bcl-2: maintenance of calcium homoeostasis is secondary to the effect of Bcl-2 on cellular glutathione

Rimpler

Rauen

Schmidt

et al. 1999

Biochemical Journal

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The oncoprotein Bcl-2 protects cells against apoptosis, but the exact molecular mechanism that underlies this function has not yet been identified. Studying H2O2-induced cell injury in Rat-1 fibroblast cells, we observed that Bcl-2 had a protective effect against the increase in cytosolic calcium concentration and subsequent cell death. Furthermore, overexpression of Bcl-2 resulted in an alteration of cellular glutathione status: the total amount of cellular glutathione was increased by about 60% and the redox potential of the cellular glutathione pool was maintained in a more reduced state during H2O2 exposure compared with non-Bcl-2-expressing controls. In our cytotoxicity model, disruption of cellular glutathione homoeostasis closely correlated with the pathological elevation of cytosolic calcium concentration. Stabilization of the glutathione pool by Bcl-2, N-acetylcysteine or glucose delayed the cytosolic calcium increase and subsequent cell death, whereas depletion of glutathione by DL-buthionine-(S,R)-sulphoximine, sensitized Bcl-2-transfected cells towards cytosolic calcium increase and cell death. We therefore suggest that the protection exerted by Bcl-2 against H2O2-induced cytosolic calcium elevation and subsequent cell death is secondary to its effect on the cellular glutathione metabolism.

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Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study

et al. 1999

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This study examines ion homeostasis in monocyte–macrophages committed to death by apoptosis. X‐ray microanalysis has been used to demonstrate that intracellular concentrations of potassium decreased whilst those of sodium increased following 3 h of exposure to 100 µg/ml of oxidized low‐density lipoprotein (LDL) in vitro. In contrast, the maximal incidence of cell death, as determined by the inability to exclude trypan blue, was not seen until 24 h of exposure. At 12 h, less than 1 per cent of cells were stained using terminal transferase‐mediated DNA nick‐end labelling, which is generally accepted as a marker of late stages in the apoptotic pathway. This is the first demonstration of early perturbations of ion homeostasis in monocyte–macrophages exposed to concentrations of oxidized LDL known to cause apoptosis. Copyright © 1999 John Wiley & Sons, Ltd.

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The role of calcium in the regulation of apoptosis

Cited by 261 publications

References 55 publications

Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Protection against hydrogen peroxide cytotoxicity in Rat-1 fibroblasts provided by the oncoprotein Bcl-2: maintenance of calcium homoeostasis is secondary to the effect of Bcl-2 on cellular glutathione

Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study

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