Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development

Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhi...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2000-06, Vol.12 (6), p.633-642
Main Authors: Yeh, W C, Itie, A, Elia, A J, Ng, M, Shu, H B, Wakeham, A, Mirtsos, C, Suzuki, N, Bonnard, M, Goeddel, D V, Mak, T W
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
Apoptosis - immunology
c-FLIP protein
Carrier Proteins - genetics
Carrier Proteins - physiology
CASP8 and FADD-Like Apoptosis Regulating Protein
Caspase 3
Caspase 8
Caspase 9
Caspases - metabolism
Casper protein
Cell Line
Embryonic and Fetal Development - genetics
Embryonic and Fetal Development - immunology
Enzyme Activation - immunology
FADD protein
Female
Heart - embryology
Intracellular Signaling Peptides and Proteins
JNK Mitogen-Activated Protein Kinases
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitogen-Activated Protein Kinases - metabolism
Myocardium - enzymology
Myocardium - immunology
Myocardium - metabolism
Myocardium - pathology
NF-kappa B - metabolism
Receptors, Tumor Necrosis Factor - physiology
Stem Cells - enzymology
Stem Cells - immunology
Stem Cells - metabolism
Stem Cells - pathology
Tumor Necrosis Factor-alpha - physiology
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Summary:Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development. This phenotype is reminiscent of that reported for FADD-/- and caspase-8-/- embryos. However, unlike FADD-/- and caspase-8-/- cells, casper-/- embryonic fibroblasts are highly sensitive to FasL- or TNF-induced apoptosis and show rapid induction of caspase activities. NF-kappaB and JNK/SAPK activation is intact in TNF-stimulated casper-/- cells. These results suggest that Casper has two distinct roles: to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis.
ISSN:1074-7613
DOI:10.1016/s1074-7613(00)80214-9