Atlas of Genetics and Cytogenetics in Oncology and Haematology


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TNFAIP3 (tumor necrosis factor, alpha-induced protein 3)

Identity

Other namesA20
MGC104522
MGC138687
MGC138688
OTUD7C
TNFA1P2
HGNC (Hugo) TNFAIP3
LocusID (NCBI) 7128
Location 6q23.3
Location_base_pair Starts at 138188325 and ends at 138204451 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order TNFAIP3 is located on chromosome 6 on the long arm (forward strand), and lies between the PERP (PERP, TP53 apoptosis effector) and OLIG3 (oligodendrocyte transcription factor 3) genes.
 
  A. Chromosomal location of TNFAIP3 gene.
B. Mapping of TNFAIP3 gene and local order on genomic context of the chromosome 6.
Note TNFAIP3 is a gene whose expression is induced by TNF (tumor necrosis factor). TNFAIP3 encodes a cytoplasmatic zinc finger protein that inhibits NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) activation and TNF-mediated apoptosis. Studies in knockout mice show that TNFAIP3 is important for limiting inflammation by terminating TNF-induced NFKB responses.

DNA/RNA

 
  Exon-intron structure of the TNFAIP3 gene. Blue boxes correspond to protein coding regions, while white boxes correspond to non coding regions.
Description TNFAIP3 is a functioning gene of 15869 bp comprising 9 exons and 8 introns. Exon 1, the 5' part of exon 2 and the 3' part of exon 9 are non coding.
Transcription Length of the transcript is 4446 bp.
Coding sequence: CDS 67-2439.
mRNA is expressed at high levels in lymph nodes, respiratory tract, larynx, trachea and kidney.

Protein

 
  Representation of the TNFAIP3 protein with localization of recognized domains. The ovarian tumor domain (OTU) is shown in green, while the seven zinc finger structures (ZNF A20) are shown in blue (UniProtKB/Swiss-Prot entry P21580).
Description Protein length of the unprocessed precursor: 790 amino acids.
Molecular weight of the unprocessed precursor: 89614 Da.
TNFAIP3 is a zinc finger protein containing seven A20-type finger motifs (E3 ubiquitin ligase domain) in its C-terminal region and a deubiquitinating enzyme domain, termed ovarian tumor (OTU) domain, in its N-terminal region. TNFAIP3 belongs to the peptidase C64 family. It is a homodimer that interacts with:
-TNIP1 (TNFAIP3 interacting protein 1, also known as Naf1 or ABIN-1),
-TAX1BP1 (Tax1 binding protein 1, also known as TXBP151 or T6BP),
-ITCH (itchy E3 ubiquitin protein ligase homolog (mouse)),
-RNF11 (ring finger protein 11),
-TRAF1, TRAF2, TRAF6 (TNF receptor-associated factor 1, 2 and 6).
Expression Expression of TNFAIP3 is induced by TNF and is repressed by PML (promyelocytic leukemia) protein.
Localisation Cytoplasm and nucleus.
Function TNFAIP3 inhibits activation of NFKB and AP-1 transcription factors, and TNF- and IL-1beta (interleukin-1beta)- induced apoptosis.
TNFAIP3 is critical for limiting inflammatory processes by terminating TNF-induced NFKB responses, and contributes to the in vivo effects of TNF.
TNFAIP3 also restricts NFKB signaling in response to stimulation of TLR (toll-like receptor) and NOD (nuclear-binding and oligomerization domain) pathways.
TNFAIP3 possesses dual ubiquitin-editing functions. In particular, the N-terminal domain of TNFAIP3 is a deubiquitinating enzyme (DUB) for Lys63-linked polyubiquitinated signaling mediators such as TRAF2/6 and RIP1 (receptor interacting protein 1). Instead, the C-terminal domain of TNFAIP3 is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the same substrates. TNFAIP3 has a specificity for particular polyubiquitinated substrates to regulate NFKB activation in the TNF, IL-1beta and TLR pathways.
TNFAIP3 has a role in the function of the lymphoid system because it inhibits NFKB signaling and may play an important role in lymphomagenesis. TNFAIP3 also negatively regulates the activity of CARD10 (caspase recruitment domain family, member 10) and BCL10 (B-cell CLL/lymphoma 10) in lymphoid and non-lymphoid cells.
A TNFAIP3-mediated inhibition of TNF-induced apoptosis is associated with the inhibition of caspase-8.
TNFAIP3 acts forming a multiprotein complex with other proteins, in particular ABIN-1, TAX1BP1, ITCH, RNF11, TRAF1, TRAF2, TRAF6, to regulate NFKB signaling cascade and TNF-induced cell death.
TNFAIP3 negatively regulates the maturation, inflammatory cytokine production and immunostimulatory potency of dendritic cells.
Homology Interspecies: ortholog to murine TNFAIP3 and homolog to Caenorhabditis elegans F21C3.2.

Mutations

Somatic Deletions and bi-allelic somatic mutations involving TNFAIP3 gene have been identified in different subtypes of B-cell lymphomas. Most of the TNFAIP3 mutations are nonsense or frameshift that prevent production of full-length TNFAIP3 protein.

Implicated in

Entity Marginal Zone B-cell Lymphoma (MZBCL)
Disease The incidence of MZBCL in the Western world is approximately 10% of all non-Hodgkin's lymphomas (NHLs). MZBCL includes three distinct clinicopathological forms:
1- Extranodal MZBCL of mucosa-associated lymphoid tissue (MALT) type,
2- Splenic MZBCL,
3- Nodal MZBCL.
The TNFAIP3 gene, that is a common genetic target in B-cell lymphomas, is frequently inactivated by somatic mutations and/or deletions in MALT lymphoma. Homozygous deletions of the chromosomal band 6q23, involving the TNFAIP3 gene, were identified in ocular adnexal MZBCLs. Inactivating mutations encoding truncated TNFAIP3 protein were also identified in extranodal, nodal and splenic MZBCLs.
Prognosis The patients usually have prolonged survival, but some cases may feature an aggressive disease. In ocular adnexal MZBCLs, TNFAIP3 deletion appears to be associated with adverse clinical parameters and with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis. TNFAIP3 deletion is also associated with a higher proportion of relapse and with a shorter relapse-free survival.
Oncogenesis TNFAIP3 inactivation by somatic mutation and/or deletion represents a genetic aberration across all MZBCL subtypes, which may contribute to lymphomagenesis by inducing constitutive NFKB activation. This suggests that TNFAIP3 may act as a tumor suppressor gene in MZBCLs.
  
Entity Classical Hodgkin's Lymphoma (cHL)
Disease cHL is a disease that involves a clonal expansion of neoplastic B lymphocytes. A constitutive NFKB activity has been detected in cHL and somatic mutations have been identified in the TNFAIP3 gene. Both TNFAIP3 alleles are inactivated, with frequent chromosomal deletion of TNFAIP3. Reconstitution of wild-type protein in TNFAIP3-deficient cHL cell lines results in a downregulation of NFKB activity and in suppression of cell growth with induction of apoptosis. In fact TNFAIP3-deficient cells generate tumours in immunodeficient mice, whereas the re-expression of TNFAIP3 suppresses the tumorigenicity.
Oncogenesis TNFAIP3 has been identified in cHL, as in other B-cell lymphomas, as a tumor suppressor gene. Loss of TNFAIP3 function, inducing a constitutive activity of NFKB, is probably involved in the pathogenesis of cHL.
  
Entity Diffuse Large B-cell Lymphoma (DLBCL)
Disease DLBCL is the most common type of lymphoma in adulthood and is a heterogeneous disease, with patients exhibiting a wide range of clinical variables, outcomes and responses to therapy. In fact DLBCL includes different biologically and clinically distinct subtypes:
- Germinal centre B-cell-like (GCB) DLBCL,
- Activated B-cell-like (ABC) DLBCL.
ABC-DLBCL, that is the most aggressive subtype, is associated with constitutive activation of NFKB. ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in TNFAIP3 gene. In fact, approximately 30% of patients display biallelic inactivation of TNFAIP3 by mutations and/or deletions. Reconstitution of TNFAIP3 induces apoptosis and cell growth arrest, indicating a tumour suppressor role of the gene.
Oncogenesis NFKB activation in DLBCL is caused by genetic lesions affecting multiple genes, including TNFAIP3. Alterations of these genes may promote lymphomagenesis by leading to abnormally prolonged NFKB responses.
  
Entity Primary Mediastinal B-cell Lymphoma (PMBL)
Disease PMBL is a subtype of DLBCL defined by a combination of clinical and pathologic features. PMBL typically presents in young female patients, that have bulky mediastinal masses with frequent invasion of adjacent structures. PMBL is a lymphoma with constitutive NFKB activity and significantly high frequency of TNFAIP3 mutations.
Oncogenesis TNFAIP3 has been identified as a tumor suppressor gene in PMBL by showing frequent somatic and clonal biallelic inactivation of the gene. Loss of TNFAIP3 function contributes to the constitutive activity of the transcription factor NFKB and the survival and/or proliferation of the cells.
  
Entity Breast cancer
Disease Breast cancer is the most common cancer among women in developed countries. The etiology is multifactorial and the majority of these tumors express estrogen receptor (ER). Tamoxifen has been shown to be an effective adjiuvant therapy for ER+ tumors, but only 60% of ER+ tumors respond to this therapy. TNFAIP3 is overexpressed in breast cancer cells and confers resistance to tamoxifen-induced cytotoxicity.
Prognosis TNFAPI3 represents a potential prognostic marker of breast cancer, because an increased expression of TNFAIP3 is associated with an aggressive phenotype of the disease.
Oncogenesis TNFAIP3 is probably a key protein involved in tamoxifen resistance in breast cancer because it is overexpressed in tamoxifen-resistant cell lines. It is a possible target for developing new strategies to prevent drug resistance in breast cancer.
  
Entity Nasopharyngeal carcinoma (NPC)
Disease TNFAIP3 expression is correlated with the differentiation stages of NPC. In particular, TNFAIP3 expression contributes to the development of undifferentiated NPC as well as poorly differentiated head and neck squamous cell carcinomas (SCCs).
Oncogenesis TNFAIP3 may have a role in the pathogenesis and aggressiveness of these tumors, probably because TNFAIP3 is implicated in survival pathways.
  

External links

Nomenclature
HGNC (Hugo)TNFAIP3   11896
Cards
AtlasTNFAIP3ID42600ch6q23
Entrez_Gene (NCBI)TNFAIP3  7128  tumor necrosis factor, alpha-induced protein 3
GeneCards (Weizmann)TNFAIP3
Ensembl (Hinxton)ENSG00000118503 [Gene_View]  chr6:138188325-138204451 [Contig_View]  TNFAIP3 [Vega]
ICGC DataPortalENSG00000118503
AceView (NCBI)TNFAIP3
Genatlas (Paris)TNFAIP3
WikiGenes7128
SOURCE (Princeton)NM_001270507 NM_001270508 NM_006290
Genomic and cartography
GoldenPath (UCSC)TNFAIP3  -  6q23.3   chr6:138188325-138204451 +  6q23-q25   [Description]    (hg19-Feb_2009)
EnsemblTNFAIP3 - 6q23-q25 [CytoView]
Mapping of homologs : NCBITNFAIP3 [Mapview]
OMIM191163   
Gene and transcription
Genbank (Entrez)AK312862 AL157444 AY820830 BC041790 BC064689
RefSeq transcript (Entrez)NM_001270507 NM_001270508 NM_006290
RefSeq genomic (Entrez)AC_000138 NC_000006 NC_018917 NG_032761 NT_025741 NW_001838990 NW_004929328
Consensus coding sequences : CCDS (NCBI)TNFAIP3
Cluster EST : UnigeneHs.211600 [ NCBI ]
CGAP (NCI)Hs.211600
Alternative Splicing : Fast-db (Paris)GSHG0026063
Alternative Splicing GalleryENSG00000118503
Gene ExpressionTNFAIP3 [ NCBI-GEO ]     TNFAIP3 [ SEEK ]   TNFAIP3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP21580 (Uniprot)
NextProtP21580  [Medical]
With graphics : InterProP21580
Splice isoforms : SwissVarP21580 (Swissvar)
Catalytic activity : Enzyme3.4.19.12 [ Enzyme-Expasy ]   3.4.19.123.4.19.12 [ IntEnz-EBI ]   3.4.19.12 [ BRENDA ]   3.4.19.12 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)OTU (PS50802)    ZF_A20 (PS51036)   
Domains : Interpro (EBI)OTU    Znf_A20   
Related proteins : CluSTrP21580
Domain families : Pfam (Sanger)OTU (PF02338)    zf-A20 (PF01754)   
Domain families : Pfam (NCBI)pfam02338    pfam01754   
Domain families : Smart (EMBL)ZnF_A20 (SM00259)  
DMDM Disease mutations7128
Blocks (Seattle)P21580
PDB (SRS)2EQE    2EQF    2EQG    2VFJ    3DKB    3OJ3    3OJ4    3VUW    3VUX    3VUY    3ZJD    3ZJE    3ZJF    3ZJG   
PDB (PDBSum)2EQE    2EQF    2EQG    2VFJ    3DKB    3OJ3    3OJ4    3VUW    3VUX    3VUY    3ZJD    3ZJE    3ZJF    3ZJG   
PDB (IMB)2EQE    2EQF    2EQG    2VFJ    3DKB    3OJ3    3OJ4    3VUW    3VUX    3VUY    3ZJD    3ZJE    3ZJF    3ZJG   
PDB (RSDB)2EQE    2EQF    2EQG    2VFJ    3DKB    3OJ3    3OJ4    3VUW    3VUX    3VUY    3ZJD    3ZJE    3ZJF    3ZJG   
Human Protein AtlasENSG00000118503
Peptide AtlasP21580
HPRD01857
IPIIPI00009448   IPI01009645   IPI01011060   IPI01011507   IPI01014095   IPI01018690   IPI00896490   IPI00973096   
Protein Interaction databases
DIP (DOE-UCLA)P21580
IntAct (EBI)P21580
FunCoupENSG00000118503
BioGRIDTNFAIP3
InParanoidP21580
Interologous Interaction database P21580
IntegromeDBTNFAIP3
STRING (EMBL)TNFAIP3
Ontologies - Pathways
Ontology : AmiGOB-1 B cell homeostasis  protease binding  response to molecule of bacterial origin  regulation of germinal center formation  negative regulation of chronic inflammatory response  DNA binding  ubiquitin thiolesterase activity  ubiquitin-protein transferase activity  ubiquitin-specific protease activity  ubiquitin-specific protease activity  protein binding  nucleus  cytoplasm  lysosome  centrosome  cytosol  proteolysis  apoptotic process  inflammatory response  zinc ion binding  protein deubiquitination  ligase activity  kinase binding  negative regulation of protein ubiquitination  negative regulation of NF-kappaB transcription factor activity  negative regulation of type I interferon production  response to muramyl dipeptide  negative regulation of interleukin-1 beta production  negative regulation of interleukin-2 production  negative regulation of interleukin-6 production  negative regulation of tumor necrosis factor production  negative regulation of toll-like receptor 2 signaling pathway  negative regulation of toll-like receptor 3 signaling pathway  negative regulation of toll-like receptor 4 signaling pathway  negative regulation of toll-like receptor 5 signaling pathway  protein K11-linked deubiquitination  nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway  negative regulation of I-kappaB kinase/NF-kappaB signaling  ubiquitin binding  protein self-association  innate immune response  positive regulation of protein catabolic process  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of bone resorption  negative regulation of innate immune response  negative regulation of smooth muscle cell proliferation  regulation of defense response to virus by host  negative regulation of inflammatory response  negative regulation of B cell activation  protein oligomerization  regulation of vascular wound healing  extracellular vesicular exosome  cellular response to hydrogen peroxide  nucleotide-binding oligomerization domain containing signaling pathway  negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway  negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway  protein K63-linked deubiquitination  protein K48-linked ubiquitination  protein K48-linked deubiquitination  cellular response to lipopolysaccharide  tolerance induction to lipopolysaccharide  negative regulation of osteoclast proliferation  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  positive regulation of hepatocyte proliferation  negative regulation of CD40 signaling pathway  negative regulation of endothelial cell apoptotic process  
Ontology : EGO-EBIB-1 B cell homeostasis  protease binding  response to molecule of bacterial origin  regulation of germinal center formation  negative regulation of chronic inflammatory response  DNA binding  ubiquitin thiolesterase activity  ubiquitin-protein transferase activity  ubiquitin-specific protease activity  ubiquitin-specific protease activity  protein binding  nucleus  cytoplasm  lysosome  centrosome  cytosol  proteolysis  apoptotic process  inflammatory response  zinc ion binding  protein deubiquitination  ligase activity  kinase binding  negative regulation of protein ubiquitination  negative regulation of NF-kappaB transcription factor activity  negative regulation of type I interferon production  response to muramyl dipeptide  negative regulation of interleukin-1 beta production  negative regulation of interleukin-2 production  negative regulation of interleukin-6 production  negative regulation of tumor necrosis factor production  negative regulation of toll-like receptor 2 signaling pathway  negative regulation of toll-like receptor 3 signaling pathway  negative regulation of toll-like receptor 4 signaling pathway  negative regulation of toll-like receptor 5 signaling pathway  protein K11-linked deubiquitination  nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway  negative regulation of I-kappaB kinase/NF-kappaB signaling  ubiquitin binding  protein self-association  innate immune response  positive regulation of protein catabolic process  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of bone resorption  negative regulation of innate immune response  negative regulation of smooth muscle cell proliferation  regulation of defense response to virus by host  negative regulation of inflammatory response  negative regulation of B cell activation  protein oligomerization  regulation of vascular wound healing  extracellular vesicular exosome  cellular response to hydrogen peroxide  nucleotide-binding oligomerization domain containing signaling pathway  negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway  negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway  protein K63-linked deubiquitination  protein K48-linked ubiquitination  protein K48-linked deubiquitination  cellular response to lipopolysaccharide  tolerance induction to lipopolysaccharide  negative regulation of osteoclast proliferation  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  positive regulation of hepatocyte proliferation  negative regulation of CD40 signaling pathway  negative regulation of endothelial cell apoptotic process  
Pathways : BIOCARTATNFR2 Signaling Pathway [Genes]    NF-kB Signaling Pathway [Genes]    CD40L Signaling Pathway [Genes]   
Pathways : KEGGNF-kappa B signaling pathway    NOD-like receptor signaling pathway    TNF signaling pathway    Measles    Epstein-Barr virus infection   
REACTOMEP21580 [protein]
REACTOME PathwaysREACT_6900 Immune System [pathway]
Protein Interaction DatabaseTNFAIP3
Wikipedia pathwaysTNFAIP3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)TNFAIP3
SNP (GeneSNP Utah)TNFAIP3
SNP : HGBaseTNFAIP3
Genetic variants : HAPMAPTNFAIP3
1000_GenomesTNFAIP3 
ICGC programENSG00000118503 
Cancer Gene: CensusTNFAIP3 
CONAN: Copy Number AnalysisTNFAIP3 
Somatic Mutations in Cancer : COSMICTNFAIP3 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
Mutations and Diseases : HGMDTNFAIP3
OMIM191163   
MedgenTNFAIP3
GENETestsTNFAIP3
Disease Genetic AssociationTNFAIP3
Huge Navigator TNFAIP3 [HugePedia]  TNFAIP3 [HugeCancerGEM]
Genomic VariantsTNFAIP3  TNFAIP3 [DGVbeta]
Exome VariantTNFAIP3
dbVarTNFAIP3
ClinVarTNFAIP3
snp3D : Map Gene to Disease7128
General knowledge
Homologs : HomoloGeneTNFAIP3
Homology/Alignments : Family Browser (UCSC)TNFAIP3
Phylogenetic Trees/Animal Genes : TreeFamTNFAIP3
Chemical/Protein Interactions : CTD7128
Chemical/Pharm GKB GenePA36593
Clinical trialTNFAIP3
Cancer Resource (Charite)ENSG00000118503
Other databases
Probes
Litterature
PubMed234 Pubmed reference(s) in Entrez
CoreMineTNFAIP3
iHOPTNFAIP3

Bibliography

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PMID 1618749
 
A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism.
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Bcl-xL functions downstream of caspase-8 to inhibit Fas- and tumor necrosis factor receptor 1-induced apoptosis of MCF7 breast carcinoma cells.
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A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells.
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TNFAIP3 is the target gene of chromosome band 6q23.3-q24.1 loss in ocular adnexal marginal zone B cell lymphoma.
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Contributor(s)

Written06-2009Silvia Rasi, Davide Rossi, Gianluca Gaidano
Division of Hematology, Department of Clinical and Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy

Citation

This paper should be referenced as such :
Rasi, S ; Rossi, D ; Gaidano, G
TNFAIP3 (tumor necrosis factor, alpha-induced protein 3)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(5):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/TNFAIP3ID42600ch6q23.html

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