Description: Homo sapiens tumor necrosis factor (TNF), mRNA. RefSeq Summary (NM_000594): This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Jul 2008]. Transcript (Including UTRs) Position: hg19 chr6:31,543,344-31,546,112 Size: 2,769 Total Exon Count: 4 Strand: + Coding Region Position: hg19 chr6:31,543,519-31,545,314 Size: 1,796 Coding Exon Count: 4
ID:TNFA_HUMAN DESCRIPTION: RecName: Full=Tumor necrosis factor; AltName: Full=Cachectin; AltName: Full=TNF-alpha; AltName: Full=Tumor necrosis factor ligand superfamily member 2; Short=TNF-a; Contains: RecName: Full=Tumor necrosis factor, membrane form; AltName: Full=N-terminal fragment; Short=NTF; Contains: RecName: Full=Intracellular domain 1; Short=ICD1; Contains: RecName: Full=Intracellular domain 2; Short=ICD2; Contains: RecName: Full=C-domain 1; Contains: RecName: Full=C-domain 2; Contains: RecName: Full=Tumor necrosis factor, soluble form; Flags: Precursor; FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. FUNCTION: The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. SUBUNIT: Homotrimer. Interacts with SPPL2B. INTERACTION: P19438:TNFRSF1A; NbExp=6; IntAct=EBI-359977, EBI-299451; SUBCELLULAR LOCATION: Cell membrane; Single-pass type II membrane protein. SUBCELLULAR LOCATION: Tumor necrosis factor, membrane form: Membrane; Single-pass type II membrane protein. SUBCELLULAR LOCATION: Tumor necrosis factor, soluble form: Secreted. SUBCELLULAR LOCATION: C-domain 1: Secreted. SUBCELLULAR LOCATION: C-domain 2: Secreted. PTM: The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C- domain 2 secreted into the extracellular space. PTM: The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1. PTM: O-glycosylated; glycans contain galactose, N- acetylgalactosamine and N-acetylneuraminic acid. POLYMORPHISM: Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424]. POLYMORPHISM: Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162]. DISEASE: Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). SIMILARITY: Belongs to the tumor necrosis factor family. SEQUENCE CAUTION: Sequence=AAF71992.1; Type=Frameshift; Positions=91, 157; Sequence=CAA75070.1; Type=Erroneous gene model prediction; WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor alpha entry; URL="http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha"; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/TNFaID319.html"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/tnf/"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/tnf/"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=TNF";
acute renal allograft rejection Lee H 2004, Influence of recipient and donor IL-1alpha, IL-4, and TNFalpha genotypes on the incidence of acute renal allograft rejection., Journal of clinical pathology. 2004 Jan;57(1):101-3.
[PubMed 14693849]
This finding argues for prospective TNFA genotyping of renal donors, with avoidance of allocation of kidneys from donors positive for the TNFA-A allele to HLA-DR mismatched recipients.
alcohol abuse Gonzalez-Quintela, A. et al. 2004, Relation of tumor necrosis factor (TNF) gene polymorphisms with serum concentrations and in vitro production of TNF-alpha and interleukin-8 in heavy drinkers., Alcohol (Fayetteville, NY). 2004 Oct-Nov;34(3-Feb):273-7.
[PubMed 15902922]
In comparison with findings for control subjects, heavy drinkers showed higher TNF-alpha production, higher IL-8 production, and higher serum IL-8 concentrations. Increased serum TNF-alpha concentrations were specifically found in heavy drinkers with the -857 (C-->T) substitution (CT heterozygotes), therefore indicating an interaction between alcohol consumption and that polymorphism on serum TNF-alpha concentrations.
allergic rhinitis Gentile, D. A. et al. 2004, Association between TNF-alpha and TGF-beta genotypes in infants and parental history of allergic rhinitis and asthma., Human immunology. 2004 Apr;65(4):347-51.
[PubMed 15120189]
These results suggest a role for TNF-alpha and TGF-beta1 genotypes in the pathogenesis of allergic rhinitis and asthma, respectively. If confirmed by future studies, cytokine genotyping may be a useful tool for identifying at-risk infants who may benefit from the selective use of preventative and/or early intervention treatments for these disorders.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P01375
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0002020 protease binding GO:0005125 cytokine activity GO:0005164 tumor necrosis factor receptor binding GO:0005515 protein binding GO:0042802 identical protein binding GO:0044212 transcription regulatory region DNA binding
Biological Process: GO:0000060 protein import into nucleus, translocation GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0000165 MAPK cascade GO:0000185 activation of MAPKKK activity GO:0000187 activation of MAPK activity GO:0001819 positive regulation of cytokine production GO:0001932 regulation of protein phosphorylation GO:0001934 positive regulation of protein phosphorylation GO:0001937 negative regulation of endothelial cell proliferation GO:0002439 chronic inflammatory response to antigenic stimulus GO:0002740 negative regulation of cytokine secretion involved in immune response GO:0002876 positive regulation of chronic inflammatory response to antigenic stimulus GO:0002925 positive regulation of humoral immune response mediated by circulating immunoglobulin GO:0006006 glucose metabolic process GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0006952 defense response GO:0006954 inflammatory response GO:0006955 immune response GO:0006959 humoral immune response GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007254 JNK cascade GO:0007275 multicellular organism development GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage GO:0009615 response to virus GO:0009651 response to salt stress GO:0009887 animal organ morphogenesis GO:0010033 response to organic substance GO:0010469 regulation of receptor activity GO:0010628 positive regulation of gene expression GO:0010629 negative regulation of gene expression GO:0010693 negative regulation of alkaline phosphatase activity GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway GO:0010888 negative regulation of lipid storage GO:0019221 cytokine-mediated signaling pathway GO:0030198 extracellular matrix organization GO:0030316 osteoclast differentiation GO:0030730 sequestering of triglyceride GO:0030866 cortical actin cytoskeleton organization GO:0031334 positive regulation of protein complex assembly GO:0031622 positive regulation of fever generation GO:0031663 lipopolysaccharide-mediated signaling pathway GO:0032715 negative regulation of interleukin-6 production GO:0032722 positive regulation of chemokine production GO:0032729 positive regulation of interferon-gamma production GO:0032755 positive regulation of interleukin-6 production GO:0032757 positive regulation of interleukin-8 production GO:0032800 receptor biosynthetic process GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034116 positive regulation of heterotypic cell-cell adhesion GO:0035509 negative regulation of myosin-light-chain-phosphatase activity GO:0042127 regulation of cell proliferation GO:0042742 defense response to bacterium GO:0043065 positive regulation of apoptotic process GO:0043068 positive regulation of programmed cell death GO:0043122 regulation of I-kappaB kinase/NF-kappaB signaling GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043242 negative regulation of protein complex disassembly GO:0043243 positive regulation of protein complex disassembly GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043406 positive regulation of MAP kinase activity GO:0043491 protein kinase B signaling GO:0043507 positive regulation of JUN kinase activity GO:0044130 negative regulation of growth of symbiont in host GO:0045071 negative regulation of viral genome replication GO:0045080 positive regulation of chemokine biosynthetic process GO:0045123 cellular extravasation GO:0045416 positive regulation of interleukin-8 biosynthetic process GO:0045429 positive regulation of nitric oxide biosynthetic process GO:0045599 negative regulation of fat cell differentiation GO:0045662 negative regulation of myoblast differentiation GO:0045668 negative regulation of osteoblast differentiation GO:0045670 regulation of osteoclast differentiation GO:0045672 positive regulation of osteoclast differentiation GO:0045732 positive regulation of protein catabolic process GO:0045785 positive regulation of cell adhesion GO:0045860 positive regulation of protein kinase activity GO:0045892 negative regulation of transcription, DNA-templated GO:0045893 positive regulation of transcription, DNA-templated GO:0045930 negative regulation of mitotic cell cycle GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0045994 positive regulation of translational initiation by iron GO:0046325 negative regulation of glucose import GO:0046330 positive regulation of JNK cascade GO:0048566 embryonic digestive tract development GO:0048661 positive regulation of smooth muscle cell proliferation GO:0050708 regulation of protein secretion GO:0050715 positive regulation of cytokine secretion GO:0050727 regulation of inflammatory response GO:0050766 positive regulation of phagocytosis GO:0050796 regulation of insulin secretion GO:0050830 defense response to Gram-positive bacterium GO:0050900 leukocyte migration GO:0050901 leukocyte tethering or rolling GO:0050995 negative regulation of lipid catabolic process GO:0051023 regulation of immunoglobulin secretion GO:0051044 positive regulation of membrane protein ectodomain proteolysis GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051222 positive regulation of protein transport GO:0051384 response to glucocorticoid GO:0051798 positive regulation of hair follicle development GO:0051897 positive regulation of protein kinase B signaling GO:0060557 positive regulation of vitamin D biosynthetic process GO:0060559 positive regulation of calcidiol 1-monooxygenase activity GO:0060664 epithelial cell proliferation involved in salivary gland morphogenesis GO:0060693 regulation of branching involved in salivary gland morphogenesis GO:0061048 negative regulation of branching involved in lung morphogenesis GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0070886 positive regulation of calcineurin-NFAT signaling cascade GO:0071222 cellular response to lipopolysaccharide GO:0071230 cellular response to amino acid stimulus GO:0071316 cellular response to nicotine GO:0071407 cellular response to organic cyclic compound GO:0071550 death-inducing signaling complex assembly GO:0071677 positive regulation of mononuclear cell migration GO:0071803 positive regulation of podosome assembly GO:0072577 endothelial cell apoptotic process GO:0072659 protein localization to plasma membrane GO:0097190 apoptotic signaling pathway GO:0097191 extrinsic apoptotic signaling pathway GO:0097527 necroptotic signaling pathway GO:1901224 positive regulation of NIK/NF-kappaB signaling GO:1901671 positive regulation of superoxide dismutase activity GO:1903140 regulation of establishment of endothelial barrier GO:1903347 negative regulation of bicellular tight junction assembly GO:1904707 positive regulation of vascular smooth muscle cell proliferation GO:1904996 positive regulation of leukocyte adhesion to vascular endothelial cell GO:1904999 positive regulation of leukocyte adhesion to arterial endothelial cell GO:2000010 positive regulation of protein localization to cell surface GO:2000304 positive regulation of ceramide biosynthetic process GO:2000334 positive regulation of blood microparticle formation GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production GO:2000377 regulation of reactive oxygen species metabolic process GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand