Ceramide: a signal for apoptosis or mitogenesis?

Kolesnick, Richard; Fuks, Zvi

doi:10.1084/jem.181.6.1949

Cited by 152 publications

(87 citation statements)

References 38 publications

(48 reference statements)

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“…In addition to the membraneassociated enzyme, another cytosolic neutral SMase independent of Mg 2ϩ has been identified and partially purified, which appears to hydrolyze intracellular sphingomyelin stores to initiate signaling (19). The signal initiated by these enzymes is then transmitted further down in the signaling cascade by activation of ceramide-activated protein phosphatases and ceramide-dependent protein kinases (13)(14)(15). In addition to the neutral SMase forms, an acidic SMase form has also been identified, displaying an pH optima around 5, the bulk of which seems to be located at the lysosomes/endosomal compartment.…”

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

“…Ceramide has attracted considerable attention due to its role as an intracellular effector molecule that mimics some of the biological effects exerted by inflammatory cytokines such as TNF (13)(14)(15)(16)(17)(18). In addition to its de novo biosynthesis, which is initiated by the condensation of serine and palmitoyl-CoA, ceramide can also be generated by sphingomyelin hydrolysis.…”

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

“…Sphingomyelinase is known to exist in two forms depending on their intracellular localization and pH optima (13)(14)(15)(16). A Mg 2ϩ -dependent membrane-bound with a neutral pH optima initiates signaling by generating ceramide at or near the vicinity of the plasma membrane.…”

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

“…Thus, enzymes that hydrolyze sphingomyelin such as sphingomyelinases stand as regulators of intracellular ceramide levels and consequently ceramide-mediated functions. These enzymes are key components of the so-called sphingomyelin pathway, an ubiquitous system that functions in transducing the signals of cytokines to the cell interior (13)(14)(15).…”

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

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Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species

Garcı́a-Ruiz¹,

Colell²,

Marı́³

et al. 1997

Journal of Biological Chemistry

765

555

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Ceramide is a sphingolipid that is generated in the signaling of inflammatory cytokines such as tumor necrosis factor (TNF), which exerts many functional roles depending on the cell type where it is produced. Since TNF cytotoxicity is mediated by overproduction of reactive oxygen species from mitochondria, we have examined the role of ceramide in generation of oxidative stress in isolated rat liver mitochondria. The present studies demonstrate that addition of N-acetylsphingosine (C 2 -ceramide) to mitochondria led to an increase of fluorescence of dihydrorhodamine 123 or dichlorofluorescein-stained mitochondria, indicating formation of hydrogen peroxide. Such effect was significant at 0.25 M and maximal at 1-5 M C 2 , decreasing at greater concentrations. This inductive effect of ceramide was mimicked by N-hexanoylsphingosine at the same concentration range, whereas the immediate precursor of C 2 , C 2 -dihydroceramide increased hydrogen peroxide at 1-5 M. Sphingosine generated hydrogen peroxide at concentrations 10 M, whereas diacylglycerol failed to increase hydrogen peroxide. The increase in hydrogen peroxide induced by C 2 was not triggered by mitochondrial permeability transition as C 2 did not induce mitochondrial swelling. Blocking electron transport chain at complex I and II prevented the increase in hydrogen peroxide induced by C 2 ; however, interruption of electron flow at complex III by antimycin A potentiated the inductive effect of C 2 . Depletion of matrix GSH prior to exposure to ceramide resulted in a potentiated increase (2-fold) of hydrogen peroxide generation, leading to lipid peroxidation and loss of activity of respiratory chain complex IV compared with GSH-repleted mitochondria. Mitochondria isolated from TNF-treated cells showed an increase (2-3-fold) in the amount of ceramide compared with mitochondria from untreated cells. These results suggest that mitochondria are a target of ceramide produced in the signaling of TNF whose effect on mitochondrial electron transport chain leads to overproduction of hydrogen peroxide and consequently this phenomena may account for the generation of reactive oxygen species during TNF cytotoxicity.

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Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

Section: From the Instituto Investigaciones Biomédicas Consejo Supermentioning

confidence: 99%

See 2 more Smart Citations

Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species

Garcı́a-Ruiz¹,

Colell²,

Marı́³

et al. 1997

Journal of Biological Chemistry

765

555

View full text Add to dashboard Cite

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“…Recently, the sphingolipid ceramide has ~een implicated in the apoptosis induced by stimulation of ::he Fas molecule [2,3] and of tumor necrosis factor (TNF) 55 kDa receptor [4]. In this model, upon occupancy of recep-:or, an intracellular sphingomyelinase would be activated by m unknown coupling mechanism, causing hydrolysis of ~phingomyelin and generation of ceramide [4][5][6]. Ceramide, n its turn, would bind to and activate several Ser/Thr protein ~inases [7] and phosphatases [8] that would connect with the ras/raf/MAP-kinase pathway [9,10].…”

Section: Introductionmentioning

confidence: 99%

CPP32 inhibition prevents Fas‐induced ceramide generation and apoptosis in human cells

et al. 1996

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Intracellular activation of sphingomyelinase, leading to ceramide generation, and ICE-like proteases have been implicated in TNF and Fas-indnced apoptosis, hut the links between these intracenular apoptotic mediators remain undef'med. We show here that a specific peptide inhibitor of the ICElike protease CPP321Yama (DEVD-cHO) blocks anti-Fasinduced apoptosis in Jurkat and U937 cells, while having no effect on TNF-indnced apoptosis in U937 cells. This peptide also prevents ceramide accumulation induced by Fas engagement. Jurkat and U937 cells, as well as their mtDNA-depleted derived lines (po cells), were sensitive to ceramide toxicity, which was not prevented by ICE-like protease inhibitors. These results, taken together, suggest that ICE-like protease activation is a prerequisite for eeramide generation and subsequent apoptosis, at least in the case of Fas-indnced cell death.

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