Tumor necrosis factor


Tumor necrosis factor
  • Cachectin
  • TNF-a
  • TNF-alpha
  • TNFA
  • TNFSF2
  • Tumor necrosis factor ligand superfamily member 2
Gene Name
Amino acid sequence
>lcl|BSEQ0001404|Tumor necrosis factor
Number of residues
Molecular Weight
Theoretical pI
GO Classification
cytokine activity / identical protein binding / protease binding / transcription regulatory region DNA binding / tumor necrosis factor receptor binding
activation of cysteine-type endopeptidase activity involved in apoptotic process / activation of MAPK activity / activation of MAPKKK activity / cell surface receptor signaling pathway / cellular response to amino acid stimulus / cellular response to nicotine / cellular response to organic cyclic compound / chronic inflammatory response to antigenic stimulus / cortical actin cytoskeleton organization / death-inducing signaling complex assembly / defense response to Gram-positive bacterium / embryonic digestive tract development / epithelial cell proliferation involved in salivary gland morphogenesis / establishment of protein localization to plasma membrane / extracellular matrix organization / extrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway via death domain receptors / glucose metabolic process / humoral immune response / I-kappaB kinase/NF-kappaB signaling / inflammatory response / intrinsic apoptotic signaling pathway in response to DNA damage / JNK cascade / leukocyte tethering or rolling / lipopolysaccharide-mediated signaling pathway / MAPK cascade / necroptotic signaling pathway / negative regulation of alkaline phosphatase activity / negative regulation of bicellular tight junction assembly / negative regulation of branching involved in lung morphogenesis / negative regulation of cytokine secretion involved in immune response / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of fat cell differentiation / negative regulation of gene expression / negative regulation of glucose import / negative regulation of growth of symbiont in host / negative regulation of interleukin-6 production / negative regulation of lipid catabolic process / negative regulation of lipid storage / negative regulation of myoblast differentiation / negative regulation of myosin-light-chain-phosphatase activity / negative regulation of osteoblast differentiation / negative regulation of protein complex disassembly / negative regulation of transcription from RNA polymerase II promoter / negative regulation of transcription, DNA-templated / negative regulation of viral genome replication / osteoclast differentiation / positive regulation of apoptotic process / positive regulation of calcidiol 1-monooxygenase activity / positive regulation of cell adhesion / positive regulation of ceramide biosynthetic process / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of chemokine biosynthetic process / positive regulation of chemokine production / positive regulation of chronic inflammatory response to antigenic stimulus / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of cytokine production / positive regulation of cytokine secretion / positive regulation of ERK1 and ERK2 cascade / positive regulation of fever generation / positive regulation of gene expression / positive regulation of hair follicle development / positive regulation of heterotypic cell-cell adhesion / positive regulation of humoral immune response mediated by circulating immunoglobulin / positive regulation of I-kappaB kinase/NF-kappaB signaling / positive regulation of interferon-gamma production / positive regulation of interleukin-6 production / positive regulation of interleukin-8 biosynthetic process / positive regulation of interleukin-8 production / positive regulation of JUN kinase activity / positive regulation of MAP kinase activity / positive regulation of membrane protein ectodomain proteolysis / positive regulation of mononuclear cell migration / positive regulation of NF-kappaB import into nucleus / positive regulation of NF-kappaB transcription factor activity / positive regulation of NFAT protein import into nucleus / positive regulation of NIK/NF-kappaB signaling / positive regulation of nitric oxide biosynthetic process / positive regulation of osteoclast differentiation / positive regulation of peptidyl-serine phosphorylation / positive regulation of phagocytosis / positive regulation of podosome assembly / positive regulation of programmed cell death / positive regulation of protein complex assembly / positive regulation of protein complex disassembly / positive regulation of protein kinase activity / positive regulation of protein kinase B signaling / positive regulation of protein localization to cell surface / positive regulation of protein phosphorylation / positive regulation of protein transport / positive regulation of sequence-specific DNA binding transcription factor activity / positive regulation of smooth muscle cell proliferation / positive regulation of transcription from RNA polymerase II promoter / positive regulation of transcription, DNA-templated / positive regulation of translational initiation by iron / positive regulation of vitamin D biosynthetic process / protein import into nucleus, translocation / protein kinase B signaling / receptor biosynthetic process / regulation of branching involved in salivary gland morphogenesis / regulation of establishment of endothelial barrier / regulation of I-kappaB kinase/NF-kappaB signaling / regulation of immunoglobulin secretion / regulation of insulin secretion / regulation of tumor necrosis factor-mediated signaling pathway / response to glucocorticoid / response to salt stress / response to virus / sequestering of triglyceride / transformed cell apoptotic process / tumor necrosis factor-mediated signaling pathway
cell surface / external side of plasma membrane / extracellular region / extracellular space / integral component of plasma membrane / membrane raft / phagocytic cup / plasma membrane / recycling endosome
General Function
Tumor necrosis factor receptor binding
Specific 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. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918).The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
Pfam Domain Function
Transmembrane Regions
Cellular Location
Cell membrane
Gene sequence
>lcl|BSEQ0021837|Tumor necrosis factor (TNF)
Chromosome Location
External Identifiers
UniProtKB IDP01375
UniProtKB Entry NameTNFA_HUMAN
GenBank Protein ID339741
GenBank Gene IDM16441
GenAtlas IDTNF
General References
  1. Nedospasov SA, Shakhov AN, Turetskaya RL, Mett VA, Azizov MM, Georgiev GP, Korobko VG, Dobrynin VN, Filippov SA, Bystrov NS, et al.: Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) in the human genome. Cold Spring Harb Symp Quant Biol. 1986;51 Pt 1:611-24. [Article]
  2. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV: Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20-1985 Jan 2;312(5996):724-9. [Article]
  3. Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB: Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature. 1985 Feb 28-Mar 6;313(6005):803-6. [Article]
  4. Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW: Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985 Sep 11;13(17):6361-73. [Article]
  5. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF: Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149-54. [Article]
  6. Marmenout A, Fransen L, Tavernier J, Van der Heyden J, Tizard R, Kawashima E, Shaw A, Johnson MJ, Semon D, Muller R, et al.: Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem. 1985 Nov 4;152(3):515-22. [Article]
  7. Iris FJ, Bougueleret L, Prieur S, Caterina D, Primas G, Perrot V, Jurka J, Rodriguez-Tome P, Claverie JM, Dausset J, et al.: Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment. Nat Genet. 1993 Feb;3(2):137-45. [Article]
  8. Neville MJ, Campbell RD: A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J Immunol. 1999 Apr 15;162(8):4745-54. [Article]
  9. Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L: Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. Genome Res. 2003 Dec;13(12):2621-36. [Article]
  10. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  11. Takakura-Yamamoto R, Yamamoto S, Fukuda S, Kurimoto M: O-glycosylated species of natural human tumor-necrosis factor-alpha. Eur J Biochem. 1996 Jan 15;235(1-2):431-7. [Article]
  12. Pocsik E, Duda E, Wallach D: Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells. J Inflamm. 1995;45(3):152-60. [Article]
  13. Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Wallach D, Roufogalis BD, Chaudhri G: A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'. EMBO J. 1999 Apr 15;18(8):2119-26. [Article]
  14. Van Ostade X, Tavernier J, Prange T, Fiers W: Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J. 1991 Apr;10(4):827-36. [Article]
  15. Stevenson FT, Bursten SL, Locksley RM, Lovett DH: Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues. J Exp Med. 1992 Oct 1;176(4):1053-62. [Article]
  16. Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD, et al.: Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997 Feb 20;385(6618):733-6. [Article]
  17. Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D: A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999 Jun;22(2):145-50. [Article]
  18. Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. [Article]
  19. Fluhrer R, Grammer G, Israel L, Condron MM, Haffner C, Friedmann E, Bohland C, Imhof A, Martoglio B, Teplow DB, Haass C: A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b. Nat Cell Biol. 2006 Aug;8(8):894-6. Epub 2006 Jul 9. [Article]
  20. Jinesh G G, Chunduru S, Kamat AM: Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-alpha but not through TRAIL and FasL. J Leukoc Biol. 2012 Jul;92(1):233-44. doi: 10.1189/jlb.1211623. Epub 2012 Apr 18. [Article]
  21. Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, Chin YE, Zhang JZ: Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med. 2013 Mar;19(3):322-8. doi: 10.1038/nm.3085. Epub 2013 Feb 10. [Article]
  22. Jones EY, Stuart DI, Walker NP: Structure of tumour necrosis factor. Nature. 1989 Mar 16;338(6212):225-8. [Article]
  23. Jones EY, Stuart DI, Walker NP: The structure of tumour necrosis factor--implications for biological function. J Cell Sci Suppl. 1990;13:11-8. [Article]
  24. Eck MJ, Sprang SR: The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding. J Biol Chem. 1989 Oct 15;264(29):17595-605. [Article]
  25. Reed C, Fu ZQ, Wu J, Xue YN, Harrison RW, Chen MJ, Weber IT: Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2. Protein Eng. 1997 Oct;10(10):1101-7. [Article]
  26. Cha SS, Kim JS, Cho HS, Shin NK, Jeong W, Shin HC, Kim YJ, Hahn JH, Oh BH: High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity. J Biol Chem. 1998 Jan 23;273(4):2153-60. [Article]
  27. Balding J, Kane D, Livingstone W, Mynett-Johnson L, Bresnihan B, Smith O, FitzGerald O: Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity. Arthritis Rheum. 2003 May;48(5):1408-13. [Article]
  28. Kim YJ, Lee HS, Yoon JH, Kim CY, Park MH, Kim LH, Park BL, Shin HD: Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection. Hum Mol Genet. 2003 Oct 1;12(19):2541-6. Epub 2003 Aug 5. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00005Etanerceptapproved, investigationalyesinhibitorantibodyDetails
DB00051Adalimumabapproved, experimentalyesinhibitorantibodyDetails
DB00608Chloroquineapproved, investigational, vet_approvedunknowninhibitorDetails
DB01407Clenbuterolapproved, investigational, vet_approvedunknownother/unknownDetails
DB05869Ethyl pyruvateinvestigationalunknownDetails
DB11967Binimetinibapproved, investigationalunknownDetails
DB08904Certolizumab pegolapprovedyesneutralizerDetails
DB00668Epinephrineapproved, vet_approvedunknownantagonistagonistDetails
DB10770Foreskin fibroblast (neonatal)approvedunknownagonistDetails
DB10772Foreskin keratinocyte (neonatal)approvedyesagonistDetails
DB13751Glycyrrhizic acidapproved, experimentalyesantagonistDetails
DB11752Bryostatin 1investigationalunknowninducerDetails
DB04297Trichostatin AexperimentalunknowndownregulatorDetails