CFLAR Research Reagents

CFLAR Background

CFLAR, short for CASP8 and FADD-like apoptosis regulator, is also known as cellular FLICE--like inhibitory protein (c-FLIP). c-FLIP is expressed constitutively in many cell types, but its lifespan is short because its expression can be regulated by a variety of stimuli ^[1]. Although many splice variants of c-FLIP have been reported at the mRNA level, only short FLIP (c-FLIPS) and long FLIP (c-FLIPL) could be detected on the protein level as so far ^[2]. As the mammalian homolog of v-FLIP (virus FLICE-like inhibitory protein), c-FLIP is structurally and sequentially homologous with caspase-8 and caspase-10 that are involved in the initiation of DR (death receptor)-induced apoptosis. c-FLIP consists of two sequential N-terminal DEDs (death effector domain), followed by a C-terminal extension containing a caspase-homologous domain analogous to caspase-8 and caspase-10. Nevertheless, c-FLIP is catalytically inactive because several amino acids conserved in caspases are substituted, such as the cysteine residue within the QACXG-motif and the histidine residue within the HG-motif ^[3][4]. c-FLIP acts as a dominant-negative inhibitor to hinder apoptosis caused by death-inducing ligands through the binding of the FAS-associated death domain (FADD) protein and/or caspases-8 and caspase-10 at the level of the death-inducing signaling complex (DISC) ^[5]. Consistently, Yeh WC et al. revealed a protective role for c-FLIP in DR-induced apoptosis of fibroblast cell lines derived from c-FLIP-knockout mice ^[6]. Since c-FLIP is a major regulator of DR-induced apoptosis, and since the aberrant c-FLIP expression is intertwined with a rising number of pathologies, detecting c-FLIP levels might be valuable to diagnosis, and drugs that only change c-FLIP-expression levels will certainly be a benefit in the treatment of relevant diseases ^[7].

[1] Micheau O, Lens S, et al. NF-kappaB signals induce the expression of c-FLIP [J]. Mol Cell Biol. 2001 Aug; 21(16):5299-305.
[2] Scaffidi C., Schmitz I., et al. The role of c-FLIP in modulation of CD95-induced apoptosis [J]. J. Biol. Chem. 1999, 274:1541-1548.
[3] Thome M, Tschopp J Regulation of lymphocyte proliferation and death by FLIP [J]. Nat Rev Immunol. 2001 Oct; 1(1):50-8.
[4] Nicholson DW, Thornberry NA Caspases: killer proteases [J]. Trends Biochem Sci. 1997 Aug; 22(8):299-306.
[5] Irmler M, Thome M, et al. Inhibition of death receptor signals by cellular FLIP [J]. Nature. 1997 Jul 10; 388(6638):190-5.
[6] Yeh WC, Itie A, et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity [J]. 2000 Jun; 12(6):633-42.
[7] Olivier Micheau. Cellular FLICE-inhibitory protein: an attractive therapeutic target?[J] Expert Opin Ther Targets. 2003 Aug; 7(4): 559-573.