5 exons; DNA size 17805 bp.

CDS: 846 nt; Krieg A. et al. (BJC 2003) reported two splice variants in neoplastic and non-neoplastic cells.

No known pseudogenes.

281 AA, 32509 Da; TRAIL (TNF-Related Apoptosis-Inducing Ligand) was originally identified by two independent groups and characterized as a member of the TNF (Tumor Necrosis Factor) family of death-inducing ligands. TRAIL can bind to five different receptors found on a variety of cell types: four membrane-bound and one soluble receptor. Two of these membrane receptors, TRAIL-R1/death receptor 4 (DR4) and TRAIL-R2/death receptor 5 (DR5), act as agonistic receptors, containing a cytoplasmic death domain through which TRAIL can transmit an apoptotic signal. The other two membrane receptors, TRAIL-R3/decoy receptor 1 (DcR1) and TRAIL-R4/decoy receptor 2 (DcR2), can also bind TRAIL, but act as antagonistic/regulatory receptors, lacking the death domain. In addition to these four transmembrane receptors, a fifth soluble antagonistic receptor, osteoprotegerin (OPG), has been identified (Diagram 1).

The extra-cellular domain of the membrane-bound TRAIL forms a bell shaped homo-trimer, much like other ligands of the TNF family. However, there is a unique insertion loop of about 16-20 amino acids in soluble TRAIL near its amino-terminal end (Diagram 2). Unlike other members of the TNF superfamily, TRAIL carries a zinc ion at the trimer interface, coordinated by the single unpaired cysteine residue (Cys 230) of each monomer (Diagram 2). This zinc ion is essential for structural integrity of TRAIL, and substituting the Cys 230 with alanine or serine strongly affects the capacity of TRAIL to induce apoptosis. Three molecules of TRAIL assemble with three molecules of the transmembrane receptor as a hexameric complex (3:3).

Membrane-bound TRAIL is expressed on the surface of activated immune cells, such as natural killer (NK) cells, T cells, macrophages and dendritic cells, whereas soluble TRAIL is present in the sera of normal individuals as well as of patients affected by neoplastic disorders. Soluble TRAIL is also released in the culture supernatant of activated peripheral blood mononuclear cells (PBMC) in response to interferon induction, so that it apparently seems to function as an immune effector molecule, mediating antitumor cytotoxicity and immune regulation. Importantly, this biological role of TRAIL is consistent with its tumor selective properties, since it implies that normal tissues are constitutively protected from circulating immune cells bearing TRAIL. Besides, a significant level of TRAIL transcript has been detected in many human tissues including thymus, spleen, PBMC, prostate, ovary, small intestine, colon and placenta, but not in the brain and it is expressed constitutively in some cell lines.

TRAIL is a type II membrane protein of about 33-35 kD, which can be cleaved from the cell surface by the aspartic proteinase cathepsin E to form a soluble ligand of about 21 kD that retains biological activity.

The best-characterized biological activity of TRAIL is to induce apoptotic cell death in a variety of neoplastic cells. Both full-length membrane expressed TRAIL and soluble TRAIL can rapidly induce apoptosis in a wide variety of human cancer cell lines and primary tumors (including hematological malignancies), showing minimal or absent cytotoxicity on normal cells, both in vitro and in vivo; thus TRAIL was identified as a potential tumor-specific cancer therapeutic. The wide expression of TRAIL and TRAIL-Rs in many normal tissues suggests that the physiological role of TRAIL is more complex than the simply induction of apoptosis in cancer cells. In this respect, several studies have demonstrated that the TRAIL-TRAIL receptors system elicit a physiological role in normal hematopoiesis (for example an anti-differentiative effect on erythroid maturation and a pro-maturative effect during megakaryocytopoiesis and in vascular physiology, promoting the survival, migration and proliferation of endothelial cells). It has also been demonstrated that TRAIL significantly counteracts the adhesion of peripheral blood derived monocytes and granulocytes to endothelial cells without inducing apoptosis in response to inflammatory cytokines in vitro, suggesting an anti-inflammatory activity of TRAIL. All these data are reviewed in Secchiero and Zauli, 2008.

GENE		IDENTITY (%)
SPECIES	SYMBOL	PROTEIN	DNA
HOMO SAPIENS	TNFSF10
VS. PAN TROGLODYTES	TNFSF10	98.9	99.3
VS. MUS MUSCULUS	TNFSF10	67.0	75.0
VS. RATTUS NORVEGICUS	TNFSF10	70.3	74.3
VS. GALLUS GALLUS	TNFSF10	59.3	64.2
VS. DANIO RERIO	TNFSF10L2	46.2	54.1

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=homologene&dopt=AlignmentScores&list_uids=2824 The homology of TRAIL with the other proteins of TNF family is reported below:

GENE		IDENTITY (%)
SPECIES	SYMBOL	PROTEIN
HOMO SAPIENS	TNFSF10
HOMO SAPIENS	TNF	23
HOMO SAPIENS	RANKL	24
HOMO SAPIENS	FASL	27
HOMO SAPIENS	CD40L	23
HOMO SAPIENS	CD137L	NOT SIGNIFICANT
HOMO SAPIENS	OX40L	NOT SIGNIFICANT
HOMO SAPIENS	CD27L	NOT SIGNIFICANT
HOMO SAPIENS	CD30L	NOT SIGNIFICANT
HOMO SAPIENS	LTA	22
HOMO SAPIENS	LTB	21
HOMO SAPIENS	APO3L	NOT SIGNIFICANT
HOMO SAPIENS	APRIL	NOT SIGNIFICANT
HOMO SAPIENS	TNFSF13B	NOT SIGNIFICANT
HOMO SAPIENS	TNFSF14	25
HOMO SAPIENS	TNFSF15	34
HOMO SAPIENS	TNFSF18	NOT SIGNIFICANT