
<ArticleTitle>Characterization of the human <prot>FLICE-inhibitory protein</prot> locus and comparison of the anti-apoptotic activity of four different <prot>flip</prot> isoforms.</ArticleTitle>
<AbstractText>Death receptor-mediated apoptosis is involved in the regulation of immune responses and in the maintenance of immunological tolerance. <prot>FLICE-inhibitory protein</prot>s (<prot>FLIP</prot>s) are important modulators of death receptor-mediated apoptosis. To date, the <prot>FLIP</prot> family encompasses multiple members, of which some are reported to be antiapoptotic and others pro-apoptotic. This led us to investigate the activity of several <prot>FLIP</prot> proteins in vitro. Concomitant with the cloning of various <prot>FLIP</prot> isoforms, a new and unexpected member of the <prot>FLIP</prot> family, denoted <prot>FLIPR</prot>, was isolated from the human Burkitt lymphoma B-cell line Raji. During the characterization of <prot>FLIPR</prot>, the genomic sequence of human <prot>FLIP</prot> was found in the NCBI GenBank. This enabled us to present the complete exon-intron constellation of the human <prot>FLIP</prot> gene and the generation of all known human <prot>FLIP</prot> isoforms by alternative splicing. We show that the human <prot>FLIP</prot> gene with a size of approximately 48 kb, consists of at least 14 exons and can give rise to 11 distinct isoforms by alternative splicing. When studying the activity of some of these isoforms, including <prot>FLIPR</prot>, they all efficiently inhibited <prot>Fas</prot>-mediated apoptosis in A20 B lymphoma cells by impeding <prot>caspase-8</prot>, -3 and -7 activity as well as <prot>poly(ADP-ribose) polymerase</prot> (<prot>PARP</prot>) cleavage.</AbstractText>
