Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase.

Cifone, Maria Grazia; Maria, Ruggero De; Roncaioli, Paola; Rippo, Maria Rita; Azuma, Miyuki; Lanier, Lewis L.; Santoni, Angela; Testi, Roberto

doi:10.1084/jem.180.4.1547

Cited by 532 publications

(298 citation statements)

References 34 publications

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“…Surprisingly, ASM activity was elevated in membrane fractions prepared from the AD brains. Although ASM is a lysosomal enzyme with important housekeeping functions, under stress conditions it may translocate from intracellular compartments to the extracellular leaflet of the cell membrane, where it hydrolyzes sphingomyelin into ceramide to form signaling platforms (Cifone et al, 1994). The ceramide-enriched platforms cluster receptor molecules, transmit apoptotic stimuli into the cell, and eventually cause cell death (Bollinger et al, 2005;Gulbins, 2003).…”

Section: Discussionmentioning

confidence: 99%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

438

468

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Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pretreatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

438

468

View full text Add to dashboard Cite

show abstract

“…If this is truly the case, the inward translocation through the membrane connection might enable cell membrane components, e.g., proteins and lipids, to migrate directly to membranes of intracellular organella, bypassing cytosolic signal cascades. Fourth, membrane perturbation such as expression of PS on the cell surface (10,11) and activation of sphingomyelinase (27)(28)(29) may contribute to cell death-associated translocation of fluorescent labels described in this report. Because FM1-43 is incorporated into the outer layer of plasma membrane (13), the dye might be able to diffuse to intracellular organella only if the molecule "flips" to the inner layer of plasma membrane (10,11).…”

Section: Discussionmentioning

confidence: 99%

Cell Death-Associated Translocation of Plasma Membrane Components Induced by CTL

Kawasaki¹,

Saitô²,

Shirota-Someya

et al. 2000

The Journal of Immunology

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In the very early stages of target cell apoptosis induced by CTL, we found that fluorescence of labeling probes of the target plasma membrane, such as N-(3-triethylammoniumpropyl)-4-(p-dibutylaminostyryl)pyridinium dibromide (FM1-43), was translocated into intracellular membrane structures including nuclear envelope and mitochondria. This translocation was associated with the execution of CTL-mediated killing, because neither the CTL-target conjugation alone nor the binding of noncytotoxic Th2 clone with target cell was sufficient to provoke the process. Although FM1-43 translocation was observed in perforin-mediated cytotoxicity, examinations with several other dyes failed to detect the evidence for membrane damages that may cause influx of the dye. Moreover, the translocation was also observed in Fas-dependent apoptosis. These data indicate that the translocation precedes the damage of plasma membrane and intracellular organella in the course of apoptotic cell death and may represent the existence of a membrane trafficking that mediates the translocation of plasma membrane components in the early onset of apoptotic cell death.

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“…PP2A is a phosphatase involved in a diverse number of pathways, such as cell cycle control. There is a cytosolic sphingomyelinase that becomes active hours after death receptor crosslinking that is responsible for a continued and persistent accumulation of ceramide (Cifone et al, 1994;Brenner et al, 1998;Chen et al, 1998). There is speculation that ceramide Initiator caspases activate by autoreactivation and transactivate executioner procaspases.…”

Section: Ceramide and Sphingomyelinase Apoptotic Signalingmentioning

confidence: 99%

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Holmes¹,

Soprano²,

Soprano³

2004

Journal Cellular Physiology

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Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N-[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR.

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Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase.

Cited by 532 publications

References 34 publications

Deregulation of sphingolipid metabolism in Alzheimer's disease

Deregulation of sphingolipid metabolism in Alzheimer's disease

Cell Death-Associated Translocation of Plasma Membrane Components Induced by CTL

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

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