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

Abstract

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-κB 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.