Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally.
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.
Varfolomeev
E E
EE
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Schuchmann
M
M
Luria
V
V
Chiannilkulchai
N
N
Beckmann
J S
JS
Mett
I L
IL
Rebrikov
D
D
Brodianski
V M
VM
Kemper
O C
OC
Kollet
O
O
Lapidot
T
T
Soffer
D
D
Sobe
T
T
Avraham
K B
KB
Goncharov
T
T
Holtmann
H
H
Lonai
P
P
Wallach
D
D
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*
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