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

Identity

Other names	APO2L
	Apo-2L
	CD253
	TL2
	TRAIL
	TRAIL-PEN
HGNC	TNFSF10
Location	3q26
Location_base_pair	Starts at 173706158 and ends at 173723963 bp from pter (hg18-Mar_2006).

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

	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 (%) 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

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	TNFSF10   11925
Entrez_Gene	TNFSF10  8743  tumor necrosis factor (ligand) superfamily, member 10
	Cards
Atlas	TNFSF10ID42632ch3q26
GeneCards	TNFSF10
Ensembl	TNFSF10 [Search_View]   ENSG00000121858 [Gene_View]
Genatlas	TNFSF10
GeneLynx	TNFSF10
eGenome	TNFSF10
euGene	8743
	Genomic and cartography
GoldenPath	TNFSF10  -  3q26   chr3:173706158-173723963 -  3q26   [Description]    (hg18-Mar_2006)
Ensembl	TNFSF10 - 3q26 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	TNFSF10
	Gene and transcription
Genbank	AK296085 [ ENTREZ ]
Genbank	AK312742 [ ENTREZ ]
Genbank	BC009795 [ ENTREZ ]
Genbank	BC020220 [ ENTREZ ]
Genbank	BC032722 [ ENTREZ ]
RefSeq	NM_003810 [ SRS ]    NM_003810 [ ENTREZ ]
RefSeq	AC_000046 [ SRS ]    AC_000046 [ ENTREZ ]
RefSeq	AC_000135 [ SRS ]    AC_000135 [ ENTREZ ]
RefSeq	NC_000003 [ SRS ]    NC_000003 [ ENTREZ ]
RefSeq	NT_005612 [ SRS ]    NT_005612 [ ENTREZ ]
RefSeq	NW_001838884 [ SRS ]    NW_001838884 [ ENTREZ ]
RefSeq	NW_921807 [ SRS ]    NW_921807 [ ENTREZ ]
AceView	TNFSF10 AceView - NCBI
Unigene	Hs.478275 [ SRS ]    Hs.478275 [ NCBI ]     HS478275 [ spliceNest ]
Fast-db	14775 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P50591 [ SRS]    P50591 [ EXPASY ]     P50591 [ INTERPRO ]     P50591 [ UNIPROT ]
Prosite	PS00251 TNF_1 [ SRS ]    PS00251 TNF_1 [ Expasy ]
Prosite	PS50049 TNF_2 [ SRS ]    PS50049 TNF_2 [ Expasy ]
Interpro	IPR017355 TNF10_TNF11 [ SRS ]    IPR017355 TNF10_TNF11 [ EBI ]
Interpro	IPR006052 TNF_family [ SRS ]    IPR006052 TNF_family [ EBI ]
Interpro	IPR008983 Tumour_necrosis_fac-like [ SRS ]    IPR008983 Tumour_necrosis_fac-like [ EBI ]
CluSTr	P50591
Pfam	PF00229 TNF [ SRS ]    PF00229 TNF [ Sanger ]    pfam00229 [ NCBI-CDD ]
Smart	SM00207 TNF [EMBL]
Prodom	PD002012 TNF_subf[INRA-Toulouse]
Prodom	P50591 TNF10_HUMAN [ Domain structure ]   P50591 TNF10_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	P50591
PDB	1D0G [ SRS ]    1D0G [ PdbSum ],   1D0G [ IMB ]   1D0G [ RSDB ]
PDB	1D2Q [ SRS ]    1D2Q [ PdbSum ],   1D2Q [ IMB ]   1D2Q [ RSDB ]
PDB	1D4V [ SRS ]    1D4V [ PdbSum ],   1D4V [ IMB ]   1D4V [ RSDB ]
PDB	1DG6 [ SRS ]    1DG6 [ PdbSum ],   1DG6 [ IMB ]   1DG6 [ RSDB ]
PDB	1DU3 [ SRS ]    1DU3 [ PdbSum ],   1DU3 [ IMB ]   1DU3 [ RSDB ]
HPRD	04670
	Protein Interaction databases
DIP	P50591
IntAct	P50591
	Polymorphism : SNP, mutations, diseases
OMIM	603598    [ map ]
GENECLINICS	603598
SNP	TNFSF10 [dbSNP-NCBI]
SNP	NM_003810 [SNP-NCI]
SNP	TNFSF10 [GeneSNPs - Utah]  TNFSF10] [HGBASE - SRS]
HAPMAP	TNFSF10 [HAPMAP]
COSMIC	TNFSF10 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	TNFSF10
	General knowledge
Family Browser	TNFSF10 [UCSC Family Browser]
SOURCE	NM_003810
SMD	Hs.478275
SAGE	Hs.478275
GO	cytokine activity [Amigo]  cytokine activity
GO	tumor necrosis factor receptor binding [Amigo]  tumor necrosis factor receptor binding
GO	extracellular region [Amigo]  extracellular region
GO	extracellular space [Amigo]  extracellular space
GO	soluble fraction [Amigo]  soluble fraction
GO	integral to plasma membrane [Amigo]  integral to plasma membrane
GO	apoptosis [Amigo]  apoptosis
GO	induction of apoptosis [Amigo]  induction of apoptosis
GO	immune response [Amigo]  immune response
GO	signal transduction [Amigo]  signal transduction
GO	cell-cell signaling [Amigo]  cell-cell signaling
GO	zinc ion binding [Amigo]  zinc ion binding
GO	activation of pro-apoptotic gene products [Amigo]  activation of pro-apoptotic gene products
GO	membrane [Amigo]  membrane
GO	positive regulation of I-kappaB kinase/NF-kappaB cascade [Amigo]  positive regulation of I-kappaB kinase/NF-kappaB cascade
GO	metal ion binding [Amigo]  metal ion binding
BIOCARTA	Induction of apoptosis through DR3 and DR4/5 Death Receptors    [Genes]
KEGG	Cytokine-cytokine receptor interaction
KEGG	Apoptosis
KEGG	Natural killer cell mediated cytotoxicity
PubGene	TNFSF10
TreeFam	TNFSF10
CTD	8743 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	TNFSF10 Related clones (RZPD - Berlin)
	PubMed
PubMed	286 Pubmed reference(s) in Entrez

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.

BogdanoviŸá AD, JankoviŸá GM, ColoviŸá MD, TrpinaŸá DP, BumbasireviŸá 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

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Contributor(s)

Written	12-2007	Maria 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. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/TNFSF10ID42632ch3q26.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Sat Oct 11 12:58:13 2008