2004
DOI: 10.1074/jbc.m310381200
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Arachidonic Acid Released by Phospholipase A2 Activation Triggers Ca2+-dependent Apoptosis through the Mitochondrial Pathway

Abstract: We studied the effects of the divalent cation ionophore A23187 on apoptotic signaling in MH1C1 cells. Addition of A23187 caused a fast rise of cytosolic Ca(2+) ([Ca(2+)](c)), which returned close to the resting level within about 40 s. The [Ca(2+)](c) rise was immediately followed by phospholipid hydrolysis, which could be inhibited by aristolochic acid or by pretreatment with thapsigargin in Ca(2+)-free medium, indicating that the Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2)) was involved. These ear… Show more

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Cited by 158 publications
(123 citation statements)
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“…4 Here, we have investigated the mechanisms whereby p66Shc primes T cells to death by the Ca 2 þ ionophore A23187, a potent inducer of apoptosis that causes PTP opening in other systems. 17 We show that p66Shc promotes T cell apoptosis both by triggering cytochrome c release and mitochondrial membrane depolarization, and by impairing Ca 2 þ homeostasis due to downregulation of plasma membrane ATPases and defective Ca 2 þ extrusion. These two independent activities, which both require Ca 2 þ -dependent p66Shc phosphorylation at S36, are likely to synergize in mediating p66Shc-dependent apoptosis.…”
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confidence: 76%
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“…4 Here, we have investigated the mechanisms whereby p66Shc primes T cells to death by the Ca 2 þ ionophore A23187, a potent inducer of apoptosis that causes PTP opening in other systems. 17 We show that p66Shc promotes T cell apoptosis both by triggering cytochrome c release and mitochondrial membrane depolarization, and by impairing Ca 2 þ homeostasis due to downregulation of plasma membrane ATPases and defective Ca 2 þ extrusion. These two independent activities, which both require Ca 2 þ -dependent p66Shc phosphorylation at S36, are likely to synergize in mediating p66Shc-dependent apoptosis.…”
mentioning
confidence: 76%
“…19 The pharmacological evidence presented suggests that PTP opening does not play a major role in p66Shc-dependent mitochondrial membrane depolarization and triggering of the intrinsic apoptotic pathway in A23187-treated T cells. This was somewhat surprising, given that A23187 activates cPLA 2 resulting in arachidonic acid production, 17 and that p66Shc increases ROS production, 9,10 events which both contribute to increase the probability of PTP opening. We cannot, however, fully exclude PTP involvement in mitochondrial depolarization, particularly in the light of the ultrastructural changes detectable after treatment with A23187.…”
Section: Discussionmentioning
confidence: 99%
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“…Recently, some studies have reported that CrTX has anti-tumor effects. However, the potential mechanism is unclear [2][3][4][5] .…”
Section: Introductionmentioning
confidence: 99%
“…There is evidence that calciumindependent PLA 2 (iPLA 2 ), which localizes to mitochondria, regulates MPTP formation based on the use of the iPLA 2 inhibitor bromoenolactone and using mitochondria from iPLA 2 ␥ knock-out mice (28 -31). The Group IVA cytosolic PLA 2 (cPLA 2 ␣) is also suggested to regulate MPTP formation and cell death by releasing arachidonic acid (32,33). Calcium regulates cPLA 2 ␣ by promoting its translocation from the cytosol to intracellular membranes although there is no evidence that it localizes to mitochondria (34,35).…”
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confidence: 99%