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Titolo:
Temporal relationships between ceramide production, caspase activation andmitochondrial dysfunction in cell lines with varying sensitivity to anti-Fas-induced apoptosis
Autore:
Rodriguez-Lafrasse, C; Alphonse, G; Broquet, P; Aloy, MT; Louisot, P; Rousson, R;
Indirizzi:
Lyon Sud Med Sch, INSERM, U189, F-69921 Oullins, France Lyon Sud Med Sch Oullins France F-69921 M, U189, F-69921 Oullins, France
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 357, anno: 2001,
parte:, 2
pagine: 407 - 416
SICI:
0264-6021(20010715)357:<407:TRBCPC>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOCHROME-C RELEASE; PERFORMANCE LIQUID-CHROMATOGRAPHY; RADIATION-INDUCED APOPTOSIS; MEDIATED APOPTOSIS; ACIDIC SPHINGOMYELINASE; GLUCOSYLCERAMIDE SYNTHASE; SIGNALING PATHWAY; GLUTATHIONE; CD95; DEATH;
Keywords:
Jurkat cells; SCC61 cells; sphingolipid metabolism; SQ20B cells;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Rodriguez-Lafrasse, C Lyon Sud Med Sch, INSERM, U189, BP12, F-69921 Oullins, France Lyon Sud Med Sch BP12 Oullins France F-69921 France
Citazione:
C. Rodriguez-Lafrasse et al., "Temporal relationships between ceramide production, caspase activation andmitochondrial dysfunction in cell lines with varying sensitivity to anti-Fas-induced apoptosis", BIOCHEM J, 357, 2001, pp. 407-416

Abstract

To clarify the chronology of events leading to anti-Fas-induced apoptosis,and the mechanisms of resistance to this death effector, we compared the response kinetics of three tumour cell lines that display varying sensitivity to anti-Fas (based on levels of apoptosis), in terms of ceramide release,mitochondrial function and the caspase-activation pathway. In the highly sensitive Jurkat cell line, early caspase-8 activation, observed from 2 h after treatment, was chronologically associated with an acute depletion of glutathione and the cleavage of caspase-3 and poly-ADP ribosyl polymerase (PARP), followed by a progressive fall in the mitochondrial transmembrane potential (Delta psi (m)), between 4 and 48 h after treatment. Ceramide levels began to increase 2 h after the addition of anti-Fas (with no increase during the first hour), and increased continuously to 640% of control cells at 48 h. In the moderately sensitive SCC61 adherent cells, comparable results were observed, though with lower levels of ceramide and a delay in the response kinetics, with apoptotic cells becoming flotant. Finally, despite early cleavage of caspase-8 at 2 h, and a sustained level of activation until 48 h, no apoptotic response was observed in anti-Fas-resistant SQ20B cells. This was confirmed by a lack of ceramide generation and mitochondrial changes, and by the absence of any detectable cleavage of caspase-3 or PARP. Inhibition of caspase processing, and amplification of endogenous ceramide signalling by pharmacological agents, allowed us to establish the order of cellular events, locating ceramide release after caspase-8 activation and before caspase-3 activation, and demonstrating a direct involvement for ceramide release in mitochondrial dysfunction. Furthermore, these experiments provide strong arguments for the role of endogenous ceramide as a key executor of apoptosis, rather than as a consequence of membrane alterations.

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Documento generato il 04/04/20 alle ore 02:26:11