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

2007-12-01   Maria Grazia Di Iasio , Elisabetta Melloni , Paola Secchiero , Silvano Capitani 

Department of Morfology, Embriology, Human Anatomy Section, Ferrara University, Italy

Identity

HGNC
LOCATION
3q26.31
LOCUSID
ALIAS
APO2L,Apo-2L,CD253,TL2,TNLG6A,TRAIL
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

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).
Atlas Image
Diagram 1. TRAIL receptor system.
Diagram 2. Schematic representation of the structure of TRAIL protein.

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) 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.

Homology

GENEIDENTITY (%)
SPECIESSYMBOL PROTEIN DNA
HOMO SAPIENSTNFSF10  
VS. PAN TROGLODYTESTNFSF1098.999.3
VS. MUS MUSCULUSTNFSF1067.075.0
VS. RATTUS NORVEGICUSTNFSF1070.374.3
VS. GALLUS GALLUSTNFSF1059.364.2
VS. DANIO RERIOTNFSF10L246.254.1
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:
GENEIDENTITY (%)
SPECIESSYMBOLPROTEIN
HOMO SAPIENSTNFSF10 
HOMO SAPIENSTNF23
HOMO SAPIENSRANKL24
HOMO SAPIENSFASL27
HOMO SAPIENSCD40L23
HOMO SAPIENSCD137LNOT SIGNIFICANT
HOMO SAPIENSOX40LNOT SIGNIFICANT
HOMO SAPIENSCD27LNOT SIGNIFICANT
HOMO SAPIENSCD30LNOT SIGNIFICANT
HOMO SAPIENSLTA22
HOMO SAPIENSLTB21
HOMO SAPIENSAPO3LNOT SIGNIFICANT
HOMO SAPIENSAPRILNOT SIGNIFICANT
HOMO SAPIENSTNFSF13BNOT SIGNIFICANT
HOMO SAPIENSTNFSF1425
HOMO SAPIENSTNFSF1534
HOMO SAPIENSTNFSF18NOT SIGNIFICANT

Mutations

Atlas Image
6 exonic variations. For details see: http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=8743

Implicated in

Entity name
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.
Entity name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
97210891998Death receptors: signaling and modulation.Ashkenazi A et al
86399331996Apoptosis in bone marrow of myelodysplastic syndrome patients.Bogdanović AD et al
156818382005Evidence for a role of TNF-related apoptosis-inducing ligand (TRAIL) in the anemia of myelodysplastic syndromes.Campioni D et al
179815332008TRAIL and osteoprotegerin: a role in endothelial physiopathology?Corallini F et al
89054471996Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily.Gruss HJ et al
103412781999Myelodysplasia.Heaney ML et al
106516272000A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL.Hymowitz SG et al
180068322007Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface.Kawakubo T et al
126448302003TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential.Krieg A et al
158280262005Functional expression of TRAIL and TRAIL-R2 during human megakaryocytic development.Melloni E et al
86631101996Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family.Pitti RM et al
118423842002Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers.Reed JC et al
180432452008Tumor-necrosis-factor-related apoptosis-inducing ligand and the regulation of hematopoiesis.Secchiero P et al
175300272007Targeting death-inducing receptors in cancer therapy.Takeda K et al
87777131995Identification and characterization of a new member of the TNF family that induces apoptosis.Wiley SR et al
167509312006The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology.Zauli G et al

Other Information

Locus ID:

NCBI: 8743
MIM: 603598
HGNC: 11925
Ensembl: ENSG00000121858

Variants:

dbSNP: 8743
ClinVar: 8743
TCGA: ENSG00000121858
COSMIC: TNFSF10

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000121858ENST00000241261P50591
ENSG00000121858ENST00000241261Q6IBA9
ENSG00000121858ENST00000420541P50591
ENSG00000121858ENST00000430881H7C246

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
ApoptosisKEGGko04210
Natural killer cell mediated cytotoxicityKEGGko04650
Cytokine-cytokine receptor interactionKEGGhsa04060
ApoptosisKEGGhsa04210
Natural killer cell mediated cytotoxicityKEGGhsa04650
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Influenza AKEGGko05164
Influenza AKEGGhsa05164
FoxO signaling pathwayKEGGhsa04068
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
TRAIL signalingREACTOMER-HSA-75158
Programmed Cell DeathREACTOMER-HSA-5357801
ApoptosisREACTOMER-HSA-109581
Caspase activation via extrinsic apoptotic signalling pathwayREACTOMER-HSA-5357769
Ligand-dependent caspase activationREACTOMER-HSA-140534
Dimerization of procaspase-8REACTOMER-HSA-69416
Regulation by c-FLIPREACTOMER-HSA-3371378
Regulated NecrosisREACTOMER-HSA-5218859
RIPK1-mediated regulated necrosisREACTOMER-HSA-5213460
Regulation of necroptotic cell deathREACTOMER-HSA-5675482
CASP8 activity is inhibitedREACTOMER-HSA-5218900

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
199626682009miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation.305
177671672007Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL.225
121182452002Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo.147
127875702003Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.147
191972432009TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells.139
194359002009Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer.137
123516342002FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer.133
186409402008Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL).131
190748312008TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5.89
179569862007HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha.86

Citation

Maria Grazia Di Iasio ; Elisabetta Melloni ; Paola Secchiero ; Silvano Capitani

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

Atlas Genet Cytogenet Oncol Haematol. 2007-12-01

Online version: http://atlasgeneticsoncology.org/gene/42632/tnfsf10