TRAIL

In the field of is_associated_with::cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a is_associated_with::protein functioning as a ligand that induces the process of cell death called is_associated_with::apoptosis.

TRAIL is a is_associated_with::cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in is_associated_with::tumor cells, by binding to certain is_associated_with::death receptors. It has been used as a target of several anti-cancer therapeutics since the mid-1990s. These however have not shown significant survival benefit.

TRAIL has also been designated CD253 (is_associated_with::cluster of differentiation 253) and TNFSF10 (is_associated_with::tumor necrosis factor (ligand) superfamily, member 10).

Gene
In humans, the gene that encodes TRAIL is located at is_associated_with::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 GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.

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 is_associated_with::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 is_associated_with::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 is_associated_with::NFkappaB. In cells expressing DcR2, TRAIL binding therefore activates is_associated_with::NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation.

Interactions
TRAIL has been shown to interact with is_associated_with::TNFRSF10B.