Cell Autonomous Apoptosis Defects in Acid Sphingomyelinase Knockout Fibroblasts

Lozano, José; Menéndez, Sílvia; Morales, Albert; Ehleiter, Desiree; Liao, Wen-Chieh; Wagman, R; Haimovitz‐Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

doi:10.1074/jbc.m006353200

Cited by 90 publications

(67 citation statements)

References 52 publications

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“…Most importantly, the sensitivity to stress could be restored in the asmaseÀ/À MEFs by administration of natural ceramide. 44 We observed that C2 ceramide, a cell-permeable analogue of ceramide, activates cell death in a number of human cell lines, as previously described in publications from many different laboratories. Quite paradoxically, we have found that C2 ceramide activates, at the same time, an NF-kBdependent survival pathway through calpain, in accordance with a previous report.…”

Section: Discussionsupporting

confidence: 72%

Ceramide triggers an NF-κB-dependent survival pathway through calpain

et al. 2005

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We have shown that C2 ceramide, a cell-permeable analog of this lipid second messenger, triggers an NF-jB dependent survival pathway that counteracts cell death. Activation of NF-jB and subsequent induction of prosurvival genes relies on calpain activity and is prevented on silencing of the calpain small subunit (Capn4) that is required for the function of ubiquitous calpains. We have demonstrated that p105 (NFjB1) and its proteolytic product p50 can be targets of microand milli-calpain in vitro and that a p50 deletion mutant, lacking both the N-and the C-terminal ends, is resistant to calpain-mediated degradation. Capn4 silencing results in stabilization of endogenous p105 and p50 in diverse human cell lines. Furthermore, p105 processing and activation of NFjB survival genes in response to C2 ceramide is impaired in Capn4À/À mouse embryonic fibroblasts defective in calpain activity. Altogether, these data argue for the existence of a ceramide-calpain-NF-jB axis with prosurvival functions.

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Section: Discussionsupporting

confidence: 72%

Ceramide triggers an NF-κB-dependent survival pathway through calpain

et al. 2005

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“…171,[302][303][304] As cells deficient for acidic SMase are still TNF sensitive, 305 TNFinduced ceramide production seems to have no general, obligatory role in TNF-induced cell death. Nevertheless, the demonstration of reduced TNFsensitivity of aSMaseÀ/À mouse embryonic fibroblasts 306 and several other studies point to aSMase and ceramide production as celltype specific modulatory factors of TNF-induced cell death. 307 TNF-R1-induced activation of aSMase occurs by a FADD-dependent, but caspase-8 independent pathway.…”

Section: Molecular Mechanisms Of Tnf-induced Cell Deathmentioning

confidence: 98%

Tumor necrosis factor signaling

2003

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A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed.

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“…The fluorogenic substrate Ac-DEVD-AFC (BD Biosciences, San Diego, USA) was used to measure caspase-3 activity according to Lozano et al [19]. Cell extracts were prepared as described by Wellington et al [20].…”

Section: Caspase-3 Activity Assaymentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

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Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

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Cell Autonomous Apoptosis Defects in Acid Sphingomyelinase Knockout Fibroblasts

Cited by 90 publications

References 52 publications

Ceramide triggers an NF-κB-dependent survival pathway through calpain

Ceramide triggers an NF-κB-dependent survival pathway through calpain

Tumor necrosis factor signaling

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

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