1998
DOI: 10.1016/s1074-7613(00)80609-3
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Targeted Disruption of the Mouse Caspase 8 Gene Ablates Cell Death Induction by the TNF Receptors, Fas/Apo1, and DR3 and Is Lethal Prenatally

Abstract: Homozygous targeted disruption of the mouse Caspase 8 (Casp8) gene was found to be lethal in utero. The Caspase 8 null embryos exhibited impaired heart muscle development and congested accumulation of erythrocytes. Recovery of hematopoietic colony-forming cells from the embryos was very low. In fibroblast strains derived from these embryos, the TNF receptors, Fas/Apo1, and DR3 were able to activate the Jun N-terminal kinase and to trigger IkappaB alpha phosphorylation and degradation. They failed, however, to … Show more

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Cited by 1,152 publications
(882 citation statements)
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“…In the absence of caspase-8 CD95-mediated apoptosis, PARP cleavage and activation of caspases was completely inhibited, whereas druginduced responses were una ected. Similar data were obtained in Jurkat cells transfected with a dominantnegative mutant of caspase-8 (data not shown) and have been recently substantiated in knock-out mice (Varfolomeev et al, 1998). These data also indicate that other receptor-associated pathways including activation of Daxx, RAIDD/caspase-2 or caspase-10 have, at least in Jurkat cells, little importance for the CD95 pathway.…”
Section: Discussionsupporting
confidence: 87%
“…In the absence of caspase-8 CD95-mediated apoptosis, PARP cleavage and activation of caspases was completely inhibited, whereas druginduced responses were una ected. Similar data were obtained in Jurkat cells transfected with a dominantnegative mutant of caspase-8 (data not shown) and have been recently substantiated in knock-out mice (Varfolomeev et al, 1998). These data also indicate that other receptor-associated pathways including activation of Daxx, RAIDD/caspase-2 or caspase-10 have, at least in Jurkat cells, little importance for the CD95 pathway.…”
Section: Discussionsupporting
confidence: 87%
“…TRADD and FADD appear to link speci®cally to the acidic form of SMase (Schwandner et al, 1998). Consistent with this observation, ®broblasts derived from the caspase 8 knockout mice were defective in Fas-and TNF-but not ceramide-induced death (Varfolomeev et al, 1998), whereas mice de®cient in Apaf-1 were totally resistant to ceramide-induced death (Cecconi et al, 1998).…”
Section: Ceramide Generation Upstream Of Caspasessupporting
confidence: 54%
“…It was suggested that membrane damage might induce cytokine receptor oligomerization, thereby initiating apoptosis. The FADD (Yeh et al, 1998) and Caspase 8 knockout mice (Varfolomeev et al, 1998), however, have clari®ed this issue as cells from these mice display normal apoptotic responses to numerous stimuli despite defects in Fas and TNF action. Similarly, stress-induced ceramide generation, when studied, appears independent of cytokine receptors.…”
Section: Ceramide Generation Upstream Of Caspasesmentioning
confidence: 99%
“…Caspase-9 de®cient T-cells of these mice are resistant to gradiation and the synthetic steroid dexamethasone, but remain sensitive to apoptosis induced by TNF-a or CD95. In contrast, caspase-8 negative cells resist CD95-and TNF-a-induced cell killing but readily die by exposure to dexamethasone or g-radiation (Varfolomeev et al, 1998). These ®ndings support the idea of several independent cell death signaling pathways (Strasser et al, 1995;Sca di et al, 1998).…”
Section: Introductionsupporting
confidence: 55%