Interleukin 1 beta-converting enzyme related proteases/caspases are involved in TRAIL-induced apoptosis of myeloma and leukemia cells

被引:134
作者
Mariani, SM
Matiba, B
Armandola, EA
Krammer, PH
机构
[1] GERMAN CANC RES CTR,DIV IMMUNOGENET,TUMOR IMMUNOL PROGRAM,D-69120 HEIDELBERG,GERMANY
[2] GERMAN CANC RES CTR,DIV IMMUNOGENET,MOL IMMUNOL PROGRAM,D-69120 HEIDELBERG,GERMANY
关键词
ANTI-FAS ANTIBODY; MEDIATED CYTOTOXICITY; POLY(ADP-RIBOSE) POLYMERASE; ICE/CED-3; PROTEASE; DEATH DOMAIN; TNF FAMILY; LIGAND; CD95; RECEPTOR; MICE;
D O I
10.1083/jcb.137.1.221
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The Fas/APO-1/CD95 ligand (CD95L) and the recently cloned TRAIL ligand belong to the TNF-family and share the ability to induce apoptosis in sensitive target cells, Little information is available on the degree of functional redundancy between these two ligands in terms of target selectivity and intracellular signalling pathway(s). To address these issues, we have expressed and characterized recombinant mouse TRAIL. Specific detection with newly developed rabbit anti-TRAIL antibodies showed that the functional TRAIL molecule released into the supernatant of recombinant baculovirus-infected Sf9 cells is very similar to that associated with the membrane fraction of Sf9 cells. CD95L resistant myeloma cells were found to be sensitive to TRAIL, displaying apoptotic features similar to those of the CD95L- and TRAIL-sensitive T leukemia cells Jurkat. To assess if IL-1 beta-converting enzyme (ICE) and/or ICE-related proteases (IRPs) (caspases) are involved in TRAIL-induced apoptosis of both cell types, peptide inhibition experiments were performed. The irreversible IRP/caspase-inhibitor Ac-YVAD-cmk and the reversible IRP/caspase-inhibitor Ac-DEVD-CHO blocked the morphological changes, disorganization of plasma membrane phospholipids, DNA fragmentation, and loss of cell viability associated with TRAIL-induced apoptosis. In addition, cells undergoing TRAIL-mediated apoptosis displayed cleavage of poly(ADP)-ribose polymerase (PARP) that was completely blocked by Ac-DEVD-CHO. These results indicate that TRAIL seems to complement the activity of the CD95 system as it allows cells, otherwise resistant, to undergo apoptosis triggered by specific extracellular ligands. Conversely, however, induction of apoptosis in sensitive cells by TRAIL involves IRPs/caspases in a fashion similar to CD95L. Thus, differential sensitivity to CD95L and TRAIL seems to map to the proximal signaling events associated with receptor triggering.
引用
收藏
页码:221 / 229
页数:9
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