title: c-FLIPR, a new regulator of death receptor-induced apoptosis.
abstract: 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.
authors.affiliation: Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Golks
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Cornelius
authors.initials: C
authors.lastname: Fritsch
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Inna N
authors.initials: IN
authors.lastname: Lavrik
mesh_terms: 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
chemical_list: 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