A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein.
The cellular FLICE-inhibitory protein (c-FLIP) is a modulator of death receptor-mediated apoptosis and plays a major role in T- and B-cell homeostasis. Three different isoforms have been described on the protein level, including the long form c-FLIP(L) as well as 2 short forms, c-FLIP(S) and the recently identified c-FLIP(R). The mechanisms controlling c-FLIP isoform production are largely unknown. Here, we identified by sequence comparison in several mammals that c-FLIP(R) and not the widely studied c-FLIP(S) is the evolutionary ancestral short c-FLIP protein. Unexpectedly, the decision for production of either c-FLIP(S) or c-FLIP(R) in humans is defined by a single nucleotide polymorphism in a 3' splice site of the c-FLIP gene (rs10190751A/G). Whereas an intact splice site directs production of c-FLIP(S), the splice-dead variant causes production of c-FLIP(R). Interestingly, due to differences in protein translation rates, higher amounts of c-FLIP(S) protein compared with c-FLIP(R) are produced. Investigation of diverse human cell lines points to an increased frequency of c-FLIP(R) in transformed B-cell lines. A comparison of 183 patients with follicular lymphoma and 233 population controls revealed an increased lymphoma risk associated with the rs10190751 A genotype causing c-FLIP(R) expression.
Institute of Molecular Medicine, University of Duesseldorf, Universitaetsstrasse 1, Duesseldorf, Germany.
Nana
N
Ueffing
Kusum K
KK
Singh
Andrea
A
Christians
Christoph
C
Thorns
Alfred C
AC
Feller
Florian
F
Nagl
Falko
F
Fend
Sebastian
S
Heikaus
Alexander
A
Marx
Rainer B
RB
Zotz
Joachim
J
Brade
Wolfgang A
WA
Schulz
Klaus
K
Schulze-Osthoff
Ingo
I
Schmitz
Christian
C
Schwerk
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis* / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease; D006801:Humans; D007700:Kinetics; D008224:Lymphoma, Follicular / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D020033:Protein Isoforms; D022821:RNA Splice Sites