Tumor Necrosis Factor-α Activates the Sphingomyelin Signal Transduction Pathway in a Cell-Free System

Dressler, Kenneth A.; Mathias, Shalini; Kolesnick, Richard

doi:10.1126/science.1313189

Cited by 415 publications

(233 citation statements)

References 41 publications

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“…A number of extracellular stimuli, not only various cytokines including tumor necrosis factor (TNF)-a, interferon-g (Kim et al, 1991;Dressler et al, 1992), interleukin-1b (Ballou et al, 1992), nerve growth factor (Dobrowsky et al, 1994), and activators of Fas receptor (Cifone et al, 1994), but also physical stresses including heat shock, irradiation and chemotherapeutic drugs (Verheij et al, 1996;Santana et al, 1996;Ja rezou et al, 1996) are shown to cause sphingomyelin (SM) hydrolysis via sphingomyelinase (SMase), leading to elevation of intracellular ceramide, although several recent reports have questioned the role of ceramide in apoptosis induced by Fas or TNF-a (Sillence and Allen, 1997; Hsu et al, 1998;Watts et al, 1997Watts et al, , 1999a. The addition of exogenous ceramide has been associated with several antiproliferative responses including cell di erentiation, apoptosis, and cell cycle arrest (Okazaki et al, 1990;Kolesnick and Hannun, 1999).…”

Section: Introductionmentioning

confidence: 99%

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

et al. 2000

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Ceramide has recently been regarded as a potential mediator of apoptosis. In the present study, the e ects of Bcl-2 and Bax on the ceramide-mediated apoptotic pathways were examined in glioma cells overexpressing Bcl-2 or Bax. Etoposide, cisplatin and tumor necrosis factor-a induced apoptosis of C6 rat glioma cells which was associated with ceramide formation due to activation of neutral sphingomyelinase, followed by release of mitochondrial cytochrome c into the cytosol and activation of caspases-9 and -3. The growth of C6 cells stably overexpressing either Bcl-2 or Bax was almost equal to that of the vector-transfected cells. Bax overexpression enhanced etoposide-induced apoptosis through acceleration of cytochrome c release and caspases activation. However, Bax had no e ect on ceramide formation. Similar ®ndings were obtained in C6 cells and U87-MG human glioblastoma cells which were transiently overexpressed with Bax. In contrast, Bcl-2 overexpression resulted in a retardation of the apoptotic process via prevention of cytochrome c release and caspases activation, and ceramide formation was also blocked when Bcl-2 was highly overexpressed in glioma cells. In addition, transient overexpression of Bcl-xL also exerted inhibitory e ects on ceramide formation and apoptotic cell death induced by etoposide. These results indicate that Bax promotes apoptosis regardless of ceramide formation and that Bcl-2 or Bcl-xL prevents ceramide formation by repressing neutral sphingomyelinase as well as ceramide-induced cytochrome c release.

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Section: Introductionmentioning

confidence: 99%

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

et al. 2000

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“…4,46,47 Interestingly, the location of the sphingomyelin pool hydrolyzed by TNF-a is controversial. Several investigators have proposed that the TNF-asensitive pool resides in the external leaflet of the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells

Karasavvas

Zakeri

1999

Cell Death Differ

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It is commonly assumed that ceramide is a second messenger that transduces signaling leading to apoptosis. We tested this hypothesis by investigating the role of ceramide in TNF-ainitiated apoptotic signaling using the histiocytic lymphoma cell line U937. We found considerable differences between cell killing by TNF-a and by ceramide. U937 cells treated with TNF-a are committed early and irreversibly to the apoptotic pathway and start to die 90 min after treatment. U937 cells treated with ceramide start to die 12 h after the initial treatment. The cell death signaling initiated by TNF-a is transduced within minutes of exposure to TNF-a and it is irreversible. Exogenous ceramide increases the intracellular level of ceramide rapidly, significantly, and well above the physiological levels, within minutes, but cellular commitment to death does not occur until after the first 6 h of incubation. Furthermore, the endogenous ceramide in U937 cells treated with TNF-a increases well after the commitment to the apoptotic pathway. The differences between ceramide and TNF-a in the kinetics and the commitment to the apoptotic pathway suggest that, (a) ceramide is not a second messenger in the apoptotic signaling of TNF-a, (b) ceramide elevations, in TNF-a treated cells, are a consequence rather than a cause of apoptosis and (c) exogenously added ceramide and TNF-a kill cells via different pathways.

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“…Since sphingolipids may be further metabolized into ceramide, a novel lipid mediator of apoptosis, in cultured cells, and since many apoptosis-inducing signals (including TNFα, chemotherapeutic drugs, Fas protein and ionizing radiation) have been demonstrated to activate apoptosis via ceramide formation [23,24], we investigated whether these sphingolipids might be converted into ceramide in order to elicit their cytocidal effects. We used the fungal agent fumonisin B1 (20 µM) to block the activity of ceramide synthase and therefore inhibit the conversion of sphingosine into ceramide, and we found that fumonisin B1 could not attenuate the apoptosis induced by sphingolipids (Table 3).…”

Section: Figure 1 Induction Of Apoptosis By Sphingosine In Hep3b Cellsmentioning

confidence: 99%

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

Hung

Chang

Chuang

1999

Biochemical Journal

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Sphingosine and other long-chain bases (including sphinganine, dimethylsphingosine and stearylamine), but not octylamine (a short-chain analogue of sphinganine), induced apoptosis in Hep3B hepatoma cells. Because both -and -erythrosphingosine and stearylamine exert potent apoptotic effects on Hep3B cells, it is possible that these long-chain bases may activate apoptosis by inhibiting protein kinase C (PKC) activity. However, pretreatment with the PKC activator PMA could not rescue cells from apoptosis triggered by long-chain bases. Therefore the involvement of PKC in this apoptotic process requires further characterization. We also investigated whether these long-chain bases might be metabolized into ceramide in order to elicit their apoptotic action. We found that long-chain bases acted independently of ceramide in the induction of apoptosis, since addition of fumonisin B1, a fungal agent which effectively inhibits ceramide synthesis from sphingosine, did not protect against apoptosis. Additionally, we found that sphingosine-

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Tumor Necrosis Factor-α Activates the Sphingomyelin Signal Transduction Pathway in a Cell-Free System

Cited by 415 publications

References 41 publications

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

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