title: Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA.
abstract: A new member of the tumor necrosis factor (TNF) cytokine family, designated Apo-2 ligand (Apo-21) [1] or TRAIL [2], has been shown recently to induce apoptosis in various tumor cell lines; however, its biological role is unknown. Here, we show that Apo-21, activated apoptosis in T-cell-enriched cultures of peripheral blood lymphocytes stimulated by interleukin-2 (IL-2), but not in unstimulated cells. This finding suggests that, like Fas/Apo-1 ligand and TNF [3-5], Apo-2L may play a role in regulating post-stimulation apoptosis of mature lymphocytes. Studies on the mechanism of Apo-2L action demonstrated marked membrane blebbing, a hallmark of apoptosis, within a few minutes of the addition of Apo-2L to tumor cells. Ectopic expression of a dominant negative mutant of FADD, a cytoplasmic protein that mediates death signalling by Fas/Apo-1 and by TNF receptor type 1 (TNFR1) [6-9], inhibited the induction of apoptosis by anti-Fas/Apo-1 antibody, but had little effect on Apo-2L function. In contrast, expression of CrmA, a cowpox virus-derived inhibitor of the Ced-2-like proteases ICE [10] and CPP32/Yama [11,12], blocked the induction of apoptosis by either Apo-2L or anti-Fas/Apo-1 antibody. These results suggest that Apo-2L activates a rapid, FADD-independent pathway to trigger a cell-death programme that requires the function of cysteine proteases such as ICE or CPP32/Yama.
authors.affiliation: Department of Molecular Oncology, Genantech Inc., South San Francisco, California 94080, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Marsters
authors.forename: R M
authors.initials: RM
authors.lastname: Pitti
authors.forename: C J
authors.initials: CJ
authors.lastname: Donahue
authors.forename: S
authors.initials: S
authors.lastname: Ruppert
authors.forename: K D
authors.initials: KD
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D015843:Serpins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014764:Viral Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D015843:Serpins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor