Review on TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10), with data on DNA, on the protein encoded, and where the gene is implicated

Capitani, S

di Iasio, MG

Melloni, E

Secchiero, P

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)  339 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology                         
                         OPEN ACCESS JOURNAL AT INIST-CNRS 
TNFSF10 (tumor necrosis factor (ligand) 
superfamily, member 10) 
Maria Grazia di Iasio, Elisabetta Melloni, Paola Secchiero, Silvano Capitani 
Signal Transduction Unit, Laboratory of Cell Biology, Section of Human Anatomy, Department of 
Morphology and Embryology, University of Ferrara, Ferrara, Italy 
Published in Atlas Database: December 2007 
Online updated version: http://AtlasGeneticsOncology.org/Genes/TNFSF10ID42632ch3q26.html  
DOI: 10.4267/2042/38559 
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. 
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Hugo: TNFSF10 
Other names: APO2L; Apo-2L; CD253; TL2; TRAIL; 
TRAIL-PEN 
Location: 3q26 
DNA/RNA 
 
 
Organization of the human TRAIL gene. 
Description 
5 exons; DNA size 17805 bp. 
Transcription 
CDS: 846 nt; Krieg A. et al. (BJC 2003) reported two 
splice variants in neoplastic and non-neoplastic cells. 
Pseudogene 
No known pseudogenes. 
Protein 
Note: 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). 
Description 
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). 
Expression 
Membrane-bound TRAIL is expressed on the surface 
of activated immune cells, such as natural killer (NK) 
 
TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) di Iasio MG, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)  340 
 
 
Diagram 1. TRAIL receptor system. 
Diagram 2. Schematic representation of the structure of TRAIL protein. 
 
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. 
Localisation 
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. 
Function 
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. 
 
TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) di Iasio MG, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)  341 
Homology  
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 
 
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 
Mutations 
 
 
6 esonic variations. For details see: http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=8743 
 
 
 
 
TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) di Iasio MG, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)  342 
Implicated in 
Myelodysplastic Syndromes (MDS) 
Note: The myelodysplastic syndromes comprise a 
heterogeneous group of clonal disorders, usually 
characterized by a normal or hypercellular marrow with 
dysplastic features leading to peripheral blood 
cytopenias and a variable incidence of transformation 
into acute myeloid leukemia (AML). Ineffective 
erythropoiesis is a common feature of MDS. One 
mechanism invoked to explain the apparent 
discrepancy between cellular marrow and peripheral 
blood cytopenias in patients with MDS is apoptosis, 
which occurs with increased frequency in MDS 
marrow. 
Disease 
The decrease of mature erythrocytes, the major clinical 
feature of MDS, has been attributed to the increased 
expression and release at the bone marrow level of 
TRAIL, that selectively inhibits erythroid development 
by specifically targeting immature erythroblasts, 
impairing erythropoiesis and contributing to the degree 
of anemia. 
B-Chronic Lymphocytic Leukemia (B-
CLL) 
Note: B-CLL represents a quintessential example of 
human malignancies that are caused primarily by 
defects in apoptosis or programmed cell death. 
During the early stages of disease, mature B 
lymphocytes that constitute most B-CLL are largely 
quiescent G(0) phase cells, which accumulate not 
because they are dividing more rapidly than normal 
cells but because they survive longer than their normal 
counterparts due to defects in the apoptotic pathways. 
These noncycling CD5+/CD19+ B lymphocytes 
accumulate in the peripheral blood, marrow, spleen, 
and lymph nodes. Defects in apoptotic pathways 
contribute also to chemoresistance, rendering tumor 
cells less sensitive to the cytotoxic actions of currently 
available anticancer drugs, and can also promote 
resistance to cellular immune responses. 
Disease 
In order to elucidate the expression of TRAIL and its 
biological potential function in B-CLL, it has been 
examined the expression of TRAIL in B-CLL PBMC in 
comparison with PBMC obtained from healthy blood 
donors as well as the susceptibility of B-CLL cells to 
soluble recombinant TRAIL and the potential effects of 
endogenous membrane-bound TRAIL on autologous 
B-CLL cell survival. It has been shown that TRAIL is 
overexpressed in B-CLL PBMC in comparison with 
normal B cells, but B-CLL cells are resistant to 
TRAIL-mediated apoptosis. Taken together, these 
findings suggest that an aberrant expression of TRAIL 
might contribute to the pathogenesis of B-CLL. 
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This article should be referenced as such: 
di Iasio MG, Melloni E, Secchiero P, Capitani S. TNFSF10 
(tumor necrosis factor (ligand) superfamily, member 10). Atlas 
Genet Cytogenet Oncol Haematol.2008;12(4):339-343. 
 
 


TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10)

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TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10)

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