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

Karasavvas, Nicos; Zakeri, Zahra

doi:10.1038/sj.cdd.4400482

Cited by 25 publications

(18 citation statements)

References 25 publications

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“…While in several stress response models ceramide generation clearly precedes apoptosis and is not inhibitable by caspase blockade, it has been questioned whether ceramide elevation during CD95 signaling occurs prior to or after the commitment step to apoptosis (21,22,40). The present studies resolve this issue.…”

Section: Discussionsupporting

confidence: 40%

“…Some investigators have reported rapid ceramide generation after activation of the 55-kDa TNF receptor or Fas/APO-1/CD95, yet others have been unable to detect early ceramide generation and hence order ceramide downstream in the apoptotic cascade (21,22). The purpose of the present investigations was to develop models in which ceramide generation could be molecularly ordered definitively with respect to CD95 signaling.…”

mentioning

confidence: 99%

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CD95(Fas/APO-1) Signals Ceramide Generation Independent of the Effector Stage of Apoptosis

Grüllich¹,

Sullards²,

Fuks³

et al. 2000

Journal of Biological Chemistry

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Although numerous studies document caspase-independent ceramide generation preceding apoptosis upon environmental stress, the molecular ordering of ceramide generation during cytokine-induced apoptosis remains uncertain. Here, we show that CD95-induced ceramide elevation occurs during the initiation phase of apoptosis. We titrated down the amount of FADD transfected into HeLa and 293T cells until it was insufficient for apoptosis, although cycloheximide (CHX) still triggered the effector phase. Even in the absence of CHX, ceramide levels increased rapidly, peaking at 2.7 ؎ 0.2-fold of control 8 h post-transfection. Dominant negative FADD failed to confer ceramide generation or CHX-mediated apoptosis. Ceramide generation induced by FADD was initiator caspase-dependent, being blocked by crmA. Limited pro-caspase 8 overexpression also increased ceramide levels 2.7 ؎ 0.2-fold, yet failed, without CHX, to initiate apoptosis. Expression of membrane-targeted oligomerized CD-8 caspase 8 induced apoptosis without CHX, yet elevated ceramide only to a level equivalent to limited pro-caspase 8 transfection. Ceramide elevations were detected concurrently by diacylglycerol kinase and electrospray tandem mass spectrometry. These investigations provide evidence that ceramide generation is initiator caspase-dependent and occurs prior to commitment to the effector phase of apoptosis, definitively ordering ceramide as proximal in CD95 signaling.

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Section: Discussionsupporting

confidence: 40%

mentioning

confidence: 99%

CD95(Fas/APO-1) Signals Ceramide Generation Independent of the Effector Stage of Apoptosis

Grüllich¹,

Sullards²,

Fuks³

et al. 2000

Journal of Biological Chemistry

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“…JNK and p38 are known to be involved in cell death induced by deprivation of nerve growth factor in PC12 cells, and by ceramide in U937 (Xia et al, 1995;Karasavvas and Zakeri 1999). In rat cerebellar granular cells, p38 has been reported to be important in glutamate-induced apoptosis (Kawasaki et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure

Jeon

Kim²,

Bae³

et al. 2000

Exp Mol Med

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Kainic acid, an analogue of glutamate, causes limbic seizures and induces cell death in the rat brain. We examined the activation of MAPK family kinases; ERKs, JNKs and p38 kinase in rat hippocampus after KA treatment. Activation of all three kinases were observed at 30 min after the treatment, but, in contrary to ERK phosphorylation, which lasted up to 3 h, the phosphorylation of JNK and p38 returned to the basal level by 2 h. The phosphorylation of upstream kinases for the MAPK family was distinct. The phosphorylation of MEK1 clearly increased at 30 min but diminished rapidly thereafter. The phosphorylation of MKK6 was also increased but reached peak at 2 h after KA treatment. However, the phosphorylation of other upstream kinases, SEK1 and MKK3, gradually decreased to 3 h after KA treatment. These results indicate that the KA activates all of the three MAPK family kinases with different time patterns and suggest the possibility that MKK3 and MKK6, and SEK1 may not be the upstream kinases for p38 and JNK in rat hippocampus.

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“…We have analyzed the effects of two intracellular messengers, the sphingomyelin-derived lipid metabolite ceramide and the short-lived radical nitric oxide (NO), by using a cell model well characterized for TNF-R1 studies, the human monocytic line U937 (4)(5)(6). In a previous study, ceramide was suggested to potentiate apoptosis induced by TNF-␣ (7).…”

mentioning

confidence: 99%

“…eath receptors [e.g., CD95; the p55 receptor for tumor necrosis factor-␣ (TNF-␣), from hereon indicated as TNF-R1; death receptors [3][4][5] are a family of transplasmalemma proteins sharing a homologous cytoplasmic domain, the death domain, responsible for initiation of the apoptotic-signaling cascade (1). Activation of death receptors triggers the assembly of DISC, composed of multiple cytosolic proteins with different functional roles (1).…”

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confidence: 99%

Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

Nadaï

Sestili

Cantoni

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

103

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Apoptosis triggered by death receptors proceeds after defined signal-transduction pathways. Whether signaling at the receptor level is regulated by intracellular messengers is still unknown. We have investigated the role of two messengers, ceramide and nitric oxide (NO), on the apoptotic pathway activated in human monocytic U937 cells by tumor necrosis factor-␣ (TNF-␣) working at its p55 receptor. Two transduction events, the receptor recruitment of the adapter protein, TRADD, and the activation of the initiator caspase, caspase 8, were investigated. When administered alone, neither of the messengers had any effect on these events. In combination with TNF-␣, however, ceramide potentiated, whereas NO inhibited, TNF-␣-induced TRADD recruitment and caspase 8 activity. The effect of NO, which was cGMP-dependent, was due to inhibition of the TNF-␣-induced generation of ceramide. Our results identify a mechanism of regulation of a signal-transduction pathway activated by death receptors.

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

Cited by 25 publications

References 25 publications

CD95(Fas/APO-1) Signals Ceramide Generation Independent of the Effector Stage of Apoptosis

CD95(Fas/APO-1) Signals Ceramide Generation Independent of the Effector Stage of Apoptosis

Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure

Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

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