c-FLIPR, a new regulator of death receptor-induced apoptosis.
c-FLIPs (c-FLICE inhibitory proteins) play an essential role in regulation of death receptor-induced apoptosis. Multiple splice variants of c-FLIP have been described on the mRNA level; so far only two of them, c-FLIP(L) and c-FLIP(S,) had been found to be expressed at the protein level. In this report, we reveal the endogenous expression of a third isoform of c-FLIP. We demonstrate its presence in a number of T and B cell lines as well as in primary human T cells. We identified this isoform as c-FLIP(R), a death effector domain-only splice variant previously identified on the mRNA level. Impor-/tantly, c-FLIP(R) is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex upon CD95 stimulation. Several properties of c-FLIP(R) are similar to c-FLIP(S): both isoforms have a short half-life, a similar pattern of expression during activation of primary human T cells, and are strongly induced in T cells upon CD3/CD28 costimulation. Taken together, our data demonstrate endogenous expression of c-FLIP(R) and similar roles of c-FLIP(R) and c-FLIP(S) isoforms in death receptor-mediated apoptosis.
Golks
Alexander
A
Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Brenner
Dirk
D
Fritsch
Cornelius
C
Krammer
Peter H
PH
Lavrik
Inna N
IN
D000911:Antibodies, Monoclonal / Q000737:chemistry; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D007438:Introns; D019169:Jurkat Cells; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens; D017252:CD3 Complex; C506386:CFLAR protein, human; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003513:Cycloheximide