title: 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 induce cell death, while doing so effectively in wild-type fibroblasts. These findings indicate that Caspase 8 plays a necessary and nonredundant role in death induction by several receptors of the TNF/NGF family and serves a vital role in embryonal development.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: E E
authors.initials: EE
authors.lastname: Varfolomeev
authors.forename: M
authors.initials: M
authors.lastname: Schuchmann
authors.forename: V
authors.initials: V
authors.lastname: Luria
authors.forename: N
authors.initials: N
authors.lastname: Chiannilkulchai
authors.forename: J S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: I L
authors.initials: IL
authors.lastname: Mett
authors.forename: D
authors.initials: D
authors.lastname: Rebrikov
authors.forename: V M
authors.initials: VM
authors.lastname: Brodianski
authors.forename: O C
authors.initials: OC
authors.lastname: Kemper
authors.forename: O
authors.initials: O
authors.lastname: Kollet
authors.forename: T
authors.initials: T
authors.lastname: Lapidot
authors.forename: D
authors.initials: D
authors.lastname: Soffer
authors.forename: T
authors.initials: T
authors.lastname: Sobe
authors.forename: K B
authors.initials: KB
authors.lastname: Avraham
authors.forename: T
authors.initials: T
authors.lastname: Goncharov
authors.forename: H
authors.initials: H
authors.lastname: Holtmann
authors.forename: P
authors.initials: P
authors.lastname: Lonai
authors.forename: D
authors.initials: D
authors.lastname: Wallach
mesh_terms: D000818:Animals; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D005313:Fetal Death / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018390:Gene Targeting; D005804:Genes, Lethal / Q000235:genetics*; D005865:Gestational Age; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000196:embryology; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D014158:Transcription, Genetic / Q000235:genetics; D019014:fas Receptor / Q000494:pharmacology / Q000502:physiology*
chemical_list: D018076:DNA, Complementary; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D019014:fas Receptor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases