Species Human Entrez 8743 | Human Mouse Ensembl ENSG00000121858 | |
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Aliases TNFSF10, APO2L, Apo-2L, CD253, TL2, TRAIL, TNLG6A, tumor necrosis factor superfamily member 10 External IDs OMIM: 603598 MGI: 107414 HomoloGene: 2824 GeneCards: TNFSF10 | ||
In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.
Contents
- Gene
- The TRAIL gene as a drug target
- Structure
- Function
- The TRAIL receptors as a drug target
- Interactions
- References
TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells, by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit.
TRAIL has also been designated CD253 (cluster of differentiation 253) and TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).
Gene
In humans, the gene that encodes TRAIL is located at chromosome 3q26, which is not close to other TNF family members. The genomic structure of the TRAIL gene spans approximately 20 kb and is composed of five exonic segments 222, 138, 42, 106, and 1245 nucleotides and four introns of approximately 8.2, 3.2, 2.3 and 2.3 kb.
The TRAIL gene lacks TATA and CAAT boxes and the promotor region contains putative response elements for transcription factors GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.
The TRAIL gene as a drug target
TIC10 (which causes expression of TRAIL) was investigated in mice with various tumour types.
Small molecule ONC201 causes expression of TRAIL which kills some cancer cells.
Structure
TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein (i.e. no leader sequence and an internal transmembrane domain). The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.
Function
TRAIL binds to the death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases. TRAIL also binds the receptors DcR1 and DcR2, which do not contain a cytoplasmic domain (DcR1) or contain a truncated death domain (DcR2). DcR1 functions as a TRAIL-neutralizing decoy-receptor. The cytoplasmic domain of DcR2 is functional and activates NFkappaB. In cells expressing DcR2, TRAIL binding therefore activates NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation.
The TRAIL receptors as a drug target
In clinical trials only a small proportion of patients responded to various drugs that targeted TRAIL death receptors.
Interactions
TRAIL has been shown to interact with TNFRSF10B.