Regulation of activation-induced Fas (CD95/Apo-1) ligand expression in T cells by the cyclin B1/Cdk1 complex.
Fas (CD95/Apo-1) ligand-mediated apoptosis has been recognized as an important mechanism of cell-mediated cytotoxicity and maintenance of immune homeostasis. Chronically activated T cells undergo activation-induced cell death (AICD), which depends on simultaneous Fas and Fas ligand expression. Previous reports have suggested that AICD might be linked to cell cycle progression of T cells and therefore to the expression of cell cycle-related molecules. In particular, cyclin B1 has been implicated in the induction of AICD in T cells. In this study, we have investigated the role of cyclin B1 in AICD and the expression of effector molecules involved in this form of cell death. Our results show that inhibition of cyclin B1 blocks AICD in T cells through specific inhibition of Fas ligand expression but not Fas-induced apoptosis. This effect of cyclin B1 appears to be mediated through the cyclin B1/cyclin-dependent kinase 1 (Cdk1/Cdc2) complex because overexpression of cyclin B1 enhances FasL promoter activity, whereas a dominant-negative version of Cdk1 blocks Fas ligand promoter induction. We provide further evidence that cyclin B1/Cdk1 regulates FasL transcription through the regulation of NFkappaB activation because dominant-negative Cdk1 inhibits activation-induced NFkappaB reporter and Rel A-induced FasL promoter activity. In conclusion, our data support a link between cell cycle progression, activation-induced Fas ligand expression, and apoptosis in T cells.
Torgler
Ralph
R
Division of Immunopathology, Institute of Pathology, University of Bern, 3010 Berne, Switzerland.
Jakob
Sabine
S
Ontsouka
Edgar
E
Nachbur
Ulrich
U
Mueller
Christoph
C
Green
Douglas R
DR
Brunner
Thomas
T
D000818:Animals; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D019926:Cyclin B / Q000378:metabolism / Q000502:physiology*; D056744:Cyclin B1; D017931:DNA Primers; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D017931:DNA Primers; D016328:NF-kappa B; D019014:fas Receptor; D016203:CDC2 Protein Kinase