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Characterization of the Human FLICE‐Inhibitory Protein Locus and Comparison of the Anti‐Apoptotic Activity of Four Different FLIP Isoforms
Author(s) -
Djerbi M.,
DarrehShori T.,
Zhivotovsky B.,
Grandien A.
Publication year - 2001
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1046/j.1365-3083.2001.00941.x
Subject(s) - flip , gene isoform , alternative splicing , biology , exon , apoptosis , gene , raji cell , poly adp ribose polymerase , intron , microbiology and biotechnology , rna splicing , genetics , cancer research , cell culture , polymerase , rna
Death receptor‐mediated apoptosis is involved in the regulation of immune responses and in the maintenance of immunological tolerance. FLICE‐inhibitory proteins (FLIPs) are important modulators of death receptor‐mediated apoptosis. To date, the FLIP 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 FLIP proteins in vitro . Concomitant with the cloning of various FLIP isoforms, a new and unexpected member of the FLIP family, denoted FLIP R , was isolated from the human Burkitt lymphoma B‐cell line Raji. During the characterization of FLIP R , the genomic sequence of human FLIP was found in the NCBI GenBank. This enabled us to present the complete exon‐intron constellation of the human FLIP gene and the generation of all known human FLIP isoforms by alternative splicing. We show that the human FLIP 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 FLIP R , they all efficiently inhibited Fas‐mediated apoptosis in A20 B lymphoma cells by impeding caspase‐8, ‐3 and ‐7 activity as well as poly(ADP‐ribose) polymerase (PARP) cleavage.