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

Gasper (c-FLIP) associates with FADD and caspase-8 in signaling complexes d ownstream of death receptors like Fas. We generated Casper-deficient mice a nd cells and noted a duality in the physiological functions of this molecul e, casper(-/-) embryos do not survive past day 10.5 of embryogenesis and ex hibit impaired heart development. This phenotype is reminiscent of that rep orted for FADD(-/-) and caspase-8(-/-) embryos. However, unlike FADD(-/-) a nd caspase-8(-/-) cells, casper(-/-) embryonic fibroblasts are highly sensi tive to FasL- or TNF-induced apoptosis and show rapid induction of caspase activities. NF-kappa B and JNK/SAPK activation is intact in TNF-stimulated casper(-/-) cells. These results suggest that Gasper has two distinct roles : to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis.