Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.

No abstract

TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli.

Cytokines in the tumor necrosis factor (TNF) family regulate development and function of the immune system. We have isolated a new member of this family, designated Apo-2 ligand (Apo-2L), via an expressed sequence tag. Apo-2L is a 281-amino acid protein, related most closely to Fas/Apo-1 ligand. Transfected Apo-2L is expressed at the cell surface with its C terminus exposed, indicating a type II transmembrane protein topology. Like Fas/Apo-1 ligand and TNF, the C-terminal extracellular region of Apo-2L (amino acids 114 -281) exhibits a homotrimeric subunit structure. Soluble Apo-2L induces extensive apoptosis in lymphoid as well as non-lymphoid tumor cell lines. The effect of Apo-2L is not inhibited by soluble Fas/Apo-1 and TNF receptors; moreover, expression of human Fas/Apo-1 in mouse fibroblasts, which confers sensitivity to induction of apoptosis by agonistic anti-Fas/Apo-1 antibody, does not confer sensitivity to Apo-2L. Hence, Apo-2L acts via a receptor which is distinct from Fas/Apo-1 and TNF receptors. These results suggest that, along with other family members such as Fas/Apo-1 ligand and TNF, Apo-2L may serve as an extracellular signal that triggers programmed cell death. TNF1 family cytokines modulate host defense mechanisms via a corresponding family of receptors (1-3). Most TNF family cytokines are expressed as type II transmembrane proteins, whose C-terminal extracellular domain is processed proteolytically to form a soluble homotrimeric molecule. In contrast, the members of the TNF receptor (TNFR) family are type I transmembrane proteins. In both families, sequence homology is found mainly in the extracellular regions, which mediate ligand-receptor binding.Members of the TNF family have diverse biological actions, including T cell co-stimulation, induction of B cell proliferation and differentiation, and macrophage activation (1-3). In addition, certain TNF family members regulate the elimination of unwanted immune cells by inducing programmed cell death (apoptosis). For example, Fas/Apo-1 ligand (Fas/Apo-1L) plays a key role in peripheral deletion of self-reactive lymphocytes, as suggested by the autoimmune phenotype of the mouse mutations lpr and gld, which occur, respectively, in the Fas/Apo-1 receptor or ligand genes (4, 5). In addition, Fas/Apo-1L is involved in apoptosis of B cells and CD4 ϩ T cells subsequent to stimulation by antigen, while TNF mediates a similar function in CD8ϩ T cells (4 -7). In this article, we describe a new member of the TNF cytokine family. We have designated this protein Apo-2L, because it resembles the Fas/Apo-1L in its amino acid sequence, as well as in its ability to induce apoptosis. Apo-2L appears to act via a receptor which is distinct from Fas/Apo-1 and TNF receptors, suggesting that its biological role is unique. EXPERIMENTAL PROCEDURESCloning of Apo-2L cDNA-To isolate a full-length cDNA that contains the sequence of expressed sequenced tag (EST) HHEA47M, a gt11 bacteriophage library of human placental cDNA (ϳ1 ϫ 10 6 clones) (HL1075b, Clontech) was screene...

No abstract

No abstract

Apo2 ligand or tumour necrosis factor-related apoptosisinducing ligand (Apo2L/TRAIL) is one of the several members of the tumour necrosis factor (TNF) gene superfamily that induce apoptosis through engagement of death receptors (DRs). Apo2L/TRAIL interacts with an unusually complex receptor system of two DRs and three decoys. This protein has garnered intense interest as a potential candidate for cancer therapy because as a trimer it selectively induces apoptosis in many transformed cells but not in normal cells. While much of the early characterisation of Apo2L/TRAIL and its receptors relied on overexpression studies, recent work using untransfected cells has clarified how endogenous proteins transmit apoptotic signals from this ligand. In this review, we focus on the apoptotic signalling pathways stimulated by Apo2L/TRAIL and summarise what is known about its physiological role.

Fas (APO-1/CD95) and tumor necrosis factor receptor 1 (TNFR1) trigger apoptosis by recruiting the apoptosis initiator caspase-8 through the adaptor FADD. Fas binds FADD directly, whereas TNFR1 binds FADD indirectly, through TRADD. TRADD alternatively recruits the NF-kappaB-inducing adaptor RIP. The TNF homolog Apo2L/TRAIL triggers apoptosis through two distinct death receptors, DR4 and DR5; however, receptor over-expression studies have yielded conflicting results on the ligand's signaling mechanism. Apo2L/TRAIL induced homomeric and heteromeric complexes of DR4 and DR5 and stimulated recruitment of FADD and caspase-8 and caspase-8 activation in nontransfected cells. TRADD and RIP, which bound TNFR1, did not bind DR4 and DR5. Thus, Apo2L/TRAIL and FasL initiate apoptosis through similar mechanisms, and FADD may be a universal adaptor for death receptors.