Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling

Wiegmann, Katja; Schütze, Stefan; Machleidt, Thomas; Witte, Dorothee; Krönke, Martin

doi:10.1016/0092-8674(94)90275-5

Cited by 687 publications

(581 citation statements)

References 49 publications

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“…Our observations in the human adenocarcinoma cell line SW480/ β-gal are compatible with reports from studies of several other cell types. Thus, TNFR1 mediated NFκB activation was found to be inhibited by NDGA in fibroblasts (SchulzeOsthoff et al, 1993), by D609 in Jurkat cells and pre-B cells (Schutze et al, 1992;Wiegmann et al, 1994) and by sodium salicylate in Jurkat cells, endothelial cells and epithelial cells (Kopp and Ghosh, 1994;Pierce et al, 1996;Schwenger et al, 1998). The resistance of TNFR2 mediated NFκB activation towards these inhibitors to our knowledge has not been previously reported.…”

Section: Discussionmentioning

confidence: 87%

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

Thommesen¹,

Lægreid²

2005

BMB Reports

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Tumor necrosis factor (TNF) signaling is mediated via two distinct receptors, TNFR2 and TNFR1, which shows partially overlapping signaling mechanisms and biological roles. In the present study, TNFR2 and TNFR1 signal transduction mechanisms involved in activation of NFκB and CMV promoter-enhancer were compared with respect to their susceptibility towards inhibitors of intracellular signaling. For this, we used SW480 cells, where we have shown that TNF-signaling can occur independently through each of the two receptors. The TNFR1 response was inhibited by D609, bromophenacyl bromide (BPB), nordihydroguararetic acid (NDGA), and by sodium salicylate, while TNFR2-mediated activation of NFκB and CMV promoter-enhancer was resistant to these compounds. The signaling mechanisms known to be affected by these inhibitors include phospholipases as well as redox-and pH-sensitive intracellular components. Our results imply that TNFR2 signaling involved in NFκB activation proceeds independently of these inhibitor-sensitive signaling components, indicating distinct signaling pathways not shared with TNFR1.

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Section: Discussionmentioning

confidence: 87%

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

Thommesen¹,

Lægreid²

2005

BMB Reports

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“…Other signalling pathways, like the activation of intracellular proteases, such as interleukin-lfl converting enzyme (ICE), recently demonstrated to be involved in Fas- [27,28] and TNF- [27] induced apoptosis, could represent the necessary cytoplasmic event to trigger cell death. The activation of an sphingomyelinase that produces the lipid mediator ceramide has been described after both Fas [29] and TNF receptor engagement [30]. The connection between membrane receptor engagement and ICE activation is still unknown, although the ceramide-activated pathway could be a common candidate for both receptors.…”

Section: Discussionmentioning

confidence: 99%

mtDNA‐depleted U937 cells are sensitive to TNF and Fas‐mediated cytototxicity

et al. 1995

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It has been proposed that TNF cytotoxicity is mediated by reactive oxygen intermediates generated by uncoupling of mitochondrial respiration. We have compared sensitive U937 cells and derived cell lines depleted of mtDNA for their ability to undergo TNF-and Fas-induced apoptosis. Cells lacking around 98% of mtDNA were still sensitive to TNF-induced apoptosis. U937 cells devoid of mtDNA (U937-p °) were resistant to TNF, but this was due to the loss of its 55 kDa receptor. U937-p ° cells were also resistant to docosahexaenoic acid, which causes U937 cell death by lipid peroxidation. These cells were sensitive to anti-Fas toxicity. The results indicate that TNF and Fasinduced toxicity occurs by a mechanism mostly independent of mitochondrial free radical generation.The mechanism by which Fas ligation triggers apoptosis, as well as a general biochemical mechanism for the apoptosis process itself, are unknown [5]. Some reports have suggested, however, the lack of implication of oxidative damage in cytotoxicity induced with anti-Fas, using antioxidants [14,15] or anaerobic conditions [16].In the present work, we have studied the effect of TNF and anti-Fas on U937 cells and in derived cell lines depleted of mtDNA by prolonged exposure to low doses of ethidium bromide. Results indicate that impairment of mitochondrial function and lipid peroxidation do not play a key role in the apoptosis induced by both molecules in human myeloid cells.

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“…These studies revealed that an 80 amino acid domain, which is localized to the Cterminal portion of the protein's intracellular region, is responsible for the generation of cytotoxic death signals, anti-viral responses (Tartaglia et al, 1993), and the activation of acid sphingomyelinase (Wiegmann et al, 1994); it is also partially responsible for, in conjunction with residues in the N-terminal portion on the intracellular region, the induction of nitric oxide (NO) synthase activity (Tartaglia et al, 1993). Homology searches have revealed that the TNF-RI death domain is approximately 65% similar (28% identical) to a 65 amino acid region within the intracellular domain of the Fas antigen; mutagenesis studies have con®rmed that these 65 amino acids are required for the induction of cell death following treatment with an anti-Fas antibody in conjunction with actinomycin D (Itoh and Nagata, 1993).…”

Section: Tnf and Tnfr Superfamiliesmentioning

confidence: 99%

Modulation of life and death by the TNF receptor superfamily

1998

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The tumor necrosis factor receptor (TNFR) superfamily represents a growing family, with over 20 members having been identi®ed thus far in mammalian cells. These proteins share signi®cant homologies in their extracellular ligand binding domains and intracellular e ector (death) domains. These receptors appear to transmit their signals via protein-protein interactions, which convey either a death or survival signal. Isolation and characterization of death domain containing proteins (TRADD, FADD/MORT-1, RIP), TRAF domain containing proteins (TRAF1-6) as well as new members and adaptor proteins such as DAXX have provided new insights to our understanding of signaling mechanisms associated with this family of receptors. While the death signals seem to be associated with the activation of both the caspase and JUN kinase pathways, the survival signals are mediated via the activation of the NF-kB pathway.

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Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling

Cited by 687 publications

References 49 publications

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

mtDNA‐depleted U937 cells are sensitive to TNF and Fas‐mediated cytototxicity

Modulation of life and death by the TNF receptor superfamily

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