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

Identity

Other namesAPO2L
Apo-2L
CD253
TL2
TRAIL
TRAIL-PEN
HGNC (Hugo) TNFSF10
LocusID (NCBI) 8743
Location 3q26.31
Location_base_pair Starts at 172223298 and ends at 172241297 bp from pter ( according to hg19-Feb_2009)  [Mapping]

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).
 
  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
GENE
IDENTITY (%)
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:
GENE
IDENTITY (%)
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

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

Implicated in

Entity 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 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.
  

External links

Nomenclature
HGNC (Hugo)TNFSF10   11925
Cards
AtlasTNFSF10ID42632ch3q26
Entrez_Gene (NCBI)TNFSF10  8743  tumor necrosis factor (ligand) superfamily, member 10
GeneCards (Weizmann)TNFSF10
Ensembl (Hinxton)ENSG00000121858 [Gene_View]  chr3:172223298-172241297 [Contig_View]  TNFSF10 [Vega]
ICGC DataPortalENSG00000121858
cBioPortalTNFSF10
AceView (NCBI)TNFSF10
Genatlas (Paris)TNFSF10
WikiGenes8743
SOURCE (Princeton)NM_001190942 NM_001190943 NM_003810
Genomic and cartography
GoldenPath (UCSC)TNFSF10  -  3q26.31   chr3:172223298-172241297 -  3q26   [Description]    (hg19-Feb_2009)
EnsemblTNFSF10 - 3q26 [CytoView]
Mapping of homologs : NCBITNFSF10 [Mapview]
OMIM603598   
Gene and transcription
Genbank (Entrez)AK296085 AK312742 AY312579 BC009795 BC020220
RefSeq transcript (Entrez)NM_001190942 NM_001190943 NM_003810
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NT_005612 NW_001838884 NW_004929311
Consensus coding sequences : CCDS (NCBI)TNFSF10
Cluster EST : UnigeneHs.478275 [ NCBI ]
CGAP (NCI)Hs.478275
Alternative Splicing : Fast-db (Paris)GSHG0022239
Alternative Splicing GalleryENSG00000121858
Gene ExpressionTNFSF10 [ NCBI-GEO ]     TNFSF10 [ SEEK ]   TNFSF10 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP50591 (Uniprot)
NextProtP50591  [Medical]
With graphics : InterProP50591
Splice isoforms : SwissVarP50591 (Swissvar)
Domaine pattern : Prosite (Expaxy)TNF_1 (PS00251)    TNF_2 (PS50049)   
Domains : Interpro (EBI)TNF_CS [organisation]   TNF_dom [organisation]   TNF_ligand_10/11 [organisation]   Tumour_necrosis_fac-like_dom [organisation]  
Related proteins : CluSTrP50591
Domain families : Pfam (Sanger)TNF (PF00229)   
Domain families : Pfam (NCBI)pfam00229   
Domain families : Smart (EMBL)TNF (SM00207)  
DMDM Disease mutations8743
Blocks (Seattle)P50591
PDB (SRS)1D0G    1D2Q    1D4V    1DG6    1DU3   
PDB (PDBSum)1D0G    1D2Q    1D4V    1DG6    1DU3   
PDB (IMB)1D0G    1D2Q    1D4V    1DG6    1DU3   
PDB (RSDB)1D0G    1D2Q    1D4V    1DG6    1DU3   
Human Protein AtlasENSG00000121858 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP50591
HPRD04670
IPIIPI00000049   IPI00926396   IPI00790933   IPI00925765   
Protein Interaction databases
DIP (DOE-UCLA)P50591
IntAct (EBI)P50591
FunCoupENSG00000121858
BioGRIDTNFSF10
InParanoidP50591
Interologous Interaction database P50591
IntegromeDBTNFSF10
STRING (EMBL)TNFSF10
Ontologies - Pathways
Ontology : AmiGOreceptor binding  cytokine activity  tumor necrosis factor receptor binding  protein binding  extracellular region  extracellular space  integral to plasma membrane  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  immune response  signal transduction  cell-cell signaling  positive regulation of apoptotic process  positive regulation of I-kappaB kinase/NF-kappaB cascade  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  metal ion binding  positive regulation of release of cytochrome c from mitochondria  apoptotic signaling pathway  positive regulation of extrinsic apoptotic signaling pathway  regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Ontology : EGO-EBIreceptor binding  cytokine activity  tumor necrosis factor receptor binding  protein binding  extracellular region  extracellular space  integral to plasma membrane  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  immune response  signal transduction  cell-cell signaling  positive regulation of apoptotic process  positive regulation of I-kappaB kinase/NF-kappaB cascade  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  metal ion binding  positive regulation of release of cytochrome c from mitochondria  apoptotic signaling pathway  positive regulation of extrinsic apoptotic signaling pathway  regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Pathways : BIOCARTAInduction of apoptosis through DR3 and DR4/5 Death Receptors [Genes]   
Pathways : KEGGCytokine-cytokine receptor interaction    FoxO signaling pathway    Apoptosis    Natural killer cell mediated cytotoxicity    Measles    Influenza A   
Protein Interaction DatabaseTNFSF10
Wikipedia pathwaysTNFSF10
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)TNFSF10
snp3D : Map Gene to Disease8743
SNP (GeneSNP Utah)TNFSF10
SNP : HGBaseTNFSF10
Genetic variants : HAPMAPTNFSF10
Exome VariantTNFSF10
1000_GenomesTNFSF10 
ICGC programENSG00000121858 
Somatic Mutations in Cancer : COSMICTNFSF10 
CONAN: Copy Number AnalysisTNFSF10 
Mutations and Diseases : HGMDTNFSF10
Genomic VariantsTNFSF10  TNFSF10 [DGVbeta]
dbVarTNFSF10
ClinVarTNFSF10
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM603598   
MedgenTNFSF10
GENETestsTNFSF10
Disease Genetic AssociationTNFSF10
Huge Navigator TNFSF10 [HugePedia]  TNFSF10 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneTNFSF10
Homology/Alignments : Family Browser (UCSC)TNFSF10
Phylogenetic Trees/Animal Genes : TreeFamTNFSF10
Chemical/Protein Interactions : CTD8743
Chemical/Pharm GKB GenePA36618
Clinical trialTNFSF10
Cancer Resource (Charite)ENSG00000121858
Other databases
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineTNFSF10
iHOPTNFSF10

Bibliography

Identification and characterization of a new member of the TNF family that induces apoptosis.
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA
Immunity. 1995 ; 3 (6) : 673-682.
PMID 8777713
 
Apoptosis in bone marrow of myelodysplastic syndrome patients.
Bogdanovičß AD, Jankovičß GM, Colovičß MD, Trpinačß DP, Bumbasirevičß VZ
Blood. 1996 ; 87 (7) : page 3064.
PMID 8639933
 
Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily.
Gruss HJ
International journal of clinical & laboratory research. 1996 ; 26 (3) : 143-159.
PMID 8905447
 
Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family.
Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A
The Journal of biological chemistry. 1996 ; 271 (22) : 12687-12690.
PMID 8663110
 
Death receptors: signaling and modulation.
Ashkenazi A, Dixit VM
Science (New York, N.Y.). 1998 ; 281 (5381) : 1305-1308.
PMID 9721089
 
Myelodysplasia.
Heaney ML, Golde DW
The New England journal of medicine. 1999 ; 340 (21) : 1649-1660.
PMID 10341278
 
Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5.
Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM
Molecular cell. 1999 ; 4 (4) : 563-571.
PMID 10549288
 
A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL.
Hymowitz SG, O'Connell MP, Ultsch MH, Hurst A, Totpal K, Ashkenazi A, de Vos AM, Kelley RF
Biochemistry. 2000 ; 39 (4) : 633-640.
PMID 10651627
 
Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers.
Reed JC, Kitada S, Kim Y, Byrd J
Seminars in oncology. 2002 ; 29 (1 Suppl 2) : 10-24.
PMID 11842384
 
TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential.
Krieg A, Krieg T, Wenzel M, Schmitt M, Ramp U, Fang B, Gabbert HE, Gerharz CD, Mahotka C
British journal of cancer. 2003 ; 88 (6) : 918-927.
PMID 12644830
 
TRAIL regulates normal erythroid maturation through an ERK-dependent pathway.
Secchiero P, Melloni E, Heikinheimo M, Mannisto S, Di Pietro R, Iacone A, Zauli G
Blood. 2004 ; 103 (2) : 517-522.
PMID 12969966
 
Evidence for a role of TNF-related apoptosis-inducing ligand (TRAIL) in the anemia of myelodysplastic syndromes.
Campioni D, Secchiero P, Corallini F, Melloni E, Capitani S, Lanza F, Zauli G
The American journal of pathology. 2005 ; 166 (2) : 557-563.
PMID 15681838
 
Functional expression of TRAIL and TRAIL-R2 during human megakaryocytic development.
Melloni E, Secchiero P, Celeghini C, Campioni D, Grill V, Guidotti L, Zauli G
Journal of cellular physiology. 2005 ; 204 (3) : 975-982.
PMID 15828026
 
TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release.
Secchiero P, Corallini F, di Iasio MG, Gonelli A, Barbarotto E, Zauli G
Blood. 2005 ; 105 (9) : 3413-3419.
PMID 15644410
 
Aberrant expression of TRAIL in B chronic lymphocytic leukemia (B-CLL) cells.
Secchiero P, Tiribelli M, Barbarotto E, Celeghini C, Michelutti A, Masolini P, Fanin R, Zauli G
Journal of cellular physiology. 2005 ; 205 (2) : 246-252.
PMID 15887227
 
The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology.
Zauli G, Secchiero P
Cytokine & growth factor reviews. 2006 ; 17 (4) : 245-257.
PMID 16750931
 
Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface.
Kawakubo T, Okamoto K, Iwata J, Shin M, Okamoto Y, Yasukochi A, Nakayama KI, Kadowaki T, Tsukuba T, Yamamoto K
Cancer research. 2007 ; 67 (22) : 10869-10878.
PMID 18006832
 
Targeting death-inducing receptors in cancer therapy.
Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ
Oncogene. 2007 ; 26 (25) : 3745-3757.
PMID 17530027
 
TRAIL and osteoprotegerin: a role in endothelial physiopathology?
Corallini F, Rimondi E, Secchiero P
Frontiers in bioscience : a journal and virtual library. 2008 ; 13 : 135-147.
PMID 17981533
 
Tumor-necrosis-factor-related apoptosis-inducing ligand and the regulation of hematopoiesis.
Secchiero P, Zauli G
Current opinion in hematology. 2008 ; 15 (1) : 42-48.
PMID 18043245
 
REVIEW articlesautomatic search in PubMed
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Contributor(s)

Written12-2007Maria Grazia di Iasio, Elisabetta Melloni, Paola Secchiero, Silvano Capitani
Department of Morfology and Embriology, Human Anatomy Section, Ferrara University, Italy

Citation

This paper 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.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/TNFSF10ID42632ch3q26.html

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indexed on : Fri Jul 11 17:07:04 CEST 2014

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